Soft Gelatin Capsules (Softgels

REVIEW Soft Gelatin Capsules (Softgels)
RAMPURNA PRASAD GULLAPALLI Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, California 94080 Received 13 December 2009; revised 15 February 2010; accepted 19 February 2010 Published online 5 April 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22151 ABSTRACT: It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability. These suboptimal properties pose signicant challenges for the oral absorption of the compounds and for the development of orally bioavailable dosage forms. Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form offers several advantages over other oral dosage forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form, delivering low and ultra-low doses of a compound, delivering a low melting compound, and minimizing potential generation of dust during manufacturing and thereby improving the safety of production personnel. However, due to the very dynamic nature of the softgel dosage form, its development and stability during its shelf-life are fraught with several challenges. The goal of the current review is to provide an in-depth discussion on the softgel dosage form to formulation scientists who are considering developing softgels for therapeutic compounds. 2010 Wiley-Liss, Inc. and the American Pharmacists Association
J Pharm Sci 99:41074148, 2010
Keywords: softgel; soft gelatin capsule; formulation; encapsulation; poorly soluble; bioavailability; cross-linking; dissolution; physical stability; chemical stability
INTRODUCTION
Oral absorption of a compound can be inuenced by a variety of factors, such as the physicochemical properties, formulation, and dose of the compound and the physiology and pathology of the gastrointestinal tract (GIT). Regardless of other factors, it is reasonable to conclude that the compound must be in the solution form or solubilized form in the GIT to diffuse into and across the enterocytes lining the intestinal lumen.1,2 The advent of combinatorial chemistry and high throughput screening (HTS) has resulted in the identication of many highly potent new chemical entities (NCEs) that usually have less than desirable physicochemical properties, that is, high molecular weight, high lipophilicity (log P), and low aqueous solubility.3 More than 40% of
The contents of this article represent the efforts and views of the author in his personal and professional capacity and do not necessarily represent the views of Elan Pharmaceuticals, Inc. and/or its afliates. Correspondence to: Rampurna Prasad Gullapalli (Telephone: 914-316-4935; Fax: 650-877-7461; E-mail: RampurnaL@gmail.com)
Journal of Pharmaceutical Sciences, Vol. 99, 41074148 (2010) 2010 Wiley-Liss, Inc. and the American Pharmacists Association
NCEs coming out of the combinatorial chemistry and HTS technologies have been thought to belong to this category.4 Poor aqueous solubility has been identied as the single largest physicochemical challenge for the oral absorption of compounds and almost inevitably leads to their lower oral bioavailabilities from the conventional dose forms.3 Traditional approaches to enhance the absorption of a compound relate to improving its solubility and rate of dissolution in the GIT uids. These approaches include using a form of the compound with optimum aqueous solubility, for example, salt form,57 amorphous form,8,9 prodrug form,10 nanosizing,1113 or employing a vehicle in which the compound is soluble and remain solubilized upon contact with the GIT aqueous environment.8,14 The least complex way to present a compound to the GIT for absorption is to administer the compound as a solution or solubilized form, thereby removing any dissolution rate-limiting step in the absorption process.2 As the compound is already in solution at the site of absorption, it could yield a faster, uniform, and enhanced absorption. Occasionally, nonaqueous (organic) vehicles are employed to solubilize poorly water soluble compounds for oral and parenteral
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use.15 Use of the nonaqueous vehicles in oral products may be complicated by many factors. First, some nonaqueous vehicles, such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), may have substantial solubilizing capacity for many compounds. However, such vehicles are not pharmaceutically acceptable. Second, some vehicles, though pharmaceutically acceptable, may not exert sufcient solubilizing action to be of any practical value for some compounds unless the dose is low. Otherwise, the volume of the vehicle required cannot be readily contained in a convenient dose unit. Third, it is also possible that precipitation of the compound from the solution may follow administration when the solubilized compound encounters the aqueous environment in the GIT, resulting in little or no absorption enhancement. When a compound demonstrates sufcient solubility in a pharmaceutically acceptable nonaqueous vehicle, soft gelatin capsules may be ideal to deliver the solution as a solid dosage form. Soft gelatin capsules (SGC), also referred to as softgels or soft elastic capsules (SEC), have gained popularity in delivering therapeutic compounds solubilized or suspended in nonaqueous vehicles. A softgel is a onepiece, hermetically sealed soft gelatin shell containing a solution, a suspension, or a semisolid, referred to as ll formulation, ll material, or ll. Softgels offer many advantages over other conventional oral dosage forms, including improving swallowbility, masking odors and unpleasant taste, protecting the encapsulated compound against oxygen and light, and able to readily dissolve in the gastric juices of the GIT. The absorption of poorly soluble compounds encapsulated in softgels may also be higher compared to that from other conventional dosage forms not only due to the solubilization of the compounds in the ll formulation but also due to the ll excipient induced inhibition of P-glycoprotein-mediated drug efux and reduced enzyme-catalyzed degradation of the compound in the lumen of the GIT.1624 Softgels also offer the advantage of accurately delivering therapeutic agents that require ultra-low doses (e.g., cardiac glycosides, vitamin D analogs). One of the major challenges in the development of the softgel dosage form is that the system is very dynamic in terms of (a) the physical migration of components between the shell and the ll and the shell and the external environment, and (b) the occurrence of physical and chemical interactions within and between the shell and ll components. It is critical to understand these intricacies to develop a softgel product that is stable and provides desired in vitro and in vivo characteristics. This review article deals with the various aspects of softgel dosage form, including selection of ll and shell compositions and manufacturing process and the inuence these
formulation and manufacturing components on the stability, dissolution, and bioavailability of the softgel dosage form. This review will be limited to only softgels prepared from gelatin and will not address softgels prepared from nongelatin material.
SOFTGEL MANUFACTURING PROCESS

The manufacturing process for the production of softgels is the rotary die process, invented by Scherer,2529 in which a molten mass of a gelatin sheath (shell) formulation at 57608C is fed from a reservoir onto two separate rotating cool casting drums (cooling drums) to form two spaced at sheets or ribbons of gelatin in a semi-molten state. Two tone softgels may be produced by utilizing two separate reservoirs of different color gelatin masses, each supplying one of the two ribbons for the cooling drums. These at ribbons are extracted from the cooling drums and are fed around rollers that lubricate them, usually with fractionated coconut oil (e.g., Miglyol1 812, Sasol; Captex1 355, Abitec)/ lecithin blend, and then brought together at a convergent angle into the nip of a pair of roller dies that include opposing die cavities. The lubrication step is necessary to avoid the sticking of ribbons together and to other machine parts. The typical speed at which a gelatin ribbon is drawn into an encapsulation station is limited to around 2.5 cm/s due to the limitation of a conventional encapsulation machine. However, higher speeds may be achieved with some modications to the encapsulation machine.30 A ll formulation, to be encapsulated, owing from its own reservoir through a tube under gravity, is fed into a positive displacement pump. Accurately metered volumes of the ll formulation are injected from a wedge (heated to 37408C) into the space between gelatin ribbons as they pass between the cavities on the die rolls. As the ribbons meet on the rim of the opposing die cavities, the bottom lips of the cavities initially seal, forming what is referred to as lower seam. The ll formulation is then injected precisely into the semi formed softgel. The softgel halves are then sealed together (forming the upper seam) by the application of heat and pressure. The heated wedge provides enough heat to the gelatin ribbons that aids in the sealing of the two-halves of a softgel. It is extremely critical to avoid entrapment of ll material within the upper seam, a concern during the encapsulation of highly viscous, viscoelastic, and stringy materials (e.g., povidone, surfactants). Such entrapment potentially results in the formation of weak seams and subsequent leakage of a softgel product. This phenomenon is not a concern in the case of the lower seam, as it has already formed before the injection of the ll material into the softgel.
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The softgels, severed around each of the die cavities, are ejected by the continuous rotation of the dies and are carried on a conveyer into a tumble dryer. The part of the gelatin sheath that is severed from the segments forming the softgels (referred to as net) is then collected for recovery and recycling of gelatin31,32 or for disposal. Photographs of softgel encapsulating machine and tumble dryer are shown in Figure 1. During the encapsulation, a series of inprocess checks such as ribbon thickness (Vernier Calipers), seam thickness (microscopy), ll weights, and shell weights are performed at regular intervals. The various steps involved in the manufacturing of a softgel product can be grouped into ve components: (a) gel mass, (b) ll formulation, (c) ribbons for encapsulation, (d) drying, and (e) nishing. The critical parameters in each manufacturing component and their effects on a softgel product are listed in Table 1. Gel Mass A gel mass (shell formulation) is usually prepared from gelatin, plasticizer(s), water, and other minor additives such as opaciers, colorants, avors, sweet-
eners, and preservatives. The gel mass is prepared by initially mixing water and plasticizer(s) with gelatin granules in a suitable reactor (kettle) to form a fully hydrated uff at room temperature. The material is then melted thoroughly at high temperatures ($90 958C) under vacuum (29.5 inch Hg) with slow mixing until a clear gel is obtained. The gel mass is then transferred into electrically heated holding tanks and kept at 57608C for encapsulation.33 If the gel formulation requires an opacier, the opacier is initially dispersed and wetted thoroughly in glycerin before its addition to the molten gel mass. Dispersion and wetting of the opacier is usually accomplished in a manufacturing setting by mixing it with glycerin in rotating drums or using drum mixers for extended periods. Other ingredients, such as colorants, avors, and preservatives, may be added and mixed at high speeds. Gelatin undergoes depolymerization when the gel mass is stored at high temperatures, resulting in a reduction of the gel strength and viscosity with time.34 Thus, the temperature and time, to which the gel mass is exposed, need to be carefully monitored and controlled throughout the encapsulation process. The gel mass is checked for clarity, color, consistency, and moisture content before encapsulation to insure that the gel will run properly on the encapsulation machine. Fill Formulation A ll formulation for encapsulation into softgels can be a solution, liquid-in-liquid dispersion, or a solid-inliquid suspension. Fill formulations are prepared using standard procedures employed in pharmaceutical solution, suspension, and semisolid manufacturing. Fill formulations after compounding are deaerated thoroughly under vacuum to eliminate any of the entrapped air in the formulation. The deaeration is a critical step in the manufacturing of a softgel product that affects not only the ll viscosity, blend uniformity, ll weight uniformity, and thus content uniformity during manufacturing, but also the physical and chemical stability of the nished softgel product during its shelf-life. Smaller scale batches of ll formulations can be deaerated in a pressure resistant stainless steel container under vacuum. Larger scale ll formulations are typically vacuum transferred into pressure resistant stainless steel tanks and further deaerated under vacuum (e.g., FrymaKoruma Vacuum Deaerator). For highly viscous ll formulations, deaeration process can be aided by moderate mixing with or without the use of heat. The length of deaeration of a ll formulation is inuenced by a variety of factors, such as the composition (e.g., lipophilic vs. hydrophilic, solution vs. suspension, presence or absence of viscosiers and surfactants), amount, and viscosity of the ll mateJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010
Figure 1. Photographs of Softgel Manufacturing Equipment. (A) Encapsulating Machine; (B) Tumble Dryer (Courtesy of Pii (Pharmaceutics International, Inc.)).
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Table 1. Critical Parameters in a Softgel Product Manufacturing

Manufacturing Component Gel Mass Parameter Composition: gelatin type and concentration, plasticizer(s) type and concentration, moisture content Process: gel aging temperature and time Composition: type (hydrophilic vs. lipophilic), solution versus suspension, particle size, morphology (suspensions), viscosiers, surfactants Process: mixing, temperature, inert environment (nitrogen blanketing, yellow lights), deaeration Cooling drums and dies speeds, cooling drums temperature, wedge temperature, ribbon thickness, softgel size Primary drying (tumble/rotary) conditions, Secondary drying (tray) conditions temperature and humidity, drying rate (air ow), drying time Sizing, polishing, printing, inspection, packaging (container-closure) Effects Gel rheology, ribbon integrity and strength, seam cutting and strength, softgel drying time, softgel hardness and brittleness, oxygen and volatile solute permeability, physical and chemical stability Fill rheology, blend and content uniformity, ll weight variation, seam integrity (due to ll trapping), softgel drying time, softgel hardness and brittleness, physical and chemical stability Fill weight variation, seam thickness and strength, production rate, drying time Fill moisture content, shell moisture content, softgel hardness and brittleness, case hardening, shell cross-linking, dissolution Product quality, physical and chemical stability
Fill Formulation
Encapsulation
Drying
Finishing
rial, deaeration temperature, and the type of deaeration equipment used. The ll formulation may be maintained at up to a maximum of 35378C at the time of encapsulation to facilitate the encapsulation process and higher temperatures should be avoided as they could interfere with the sealing of softgels. Fill formulations which are viscoelastic (stringy), shear sensitive (shear-thickening or dilatant material), and solidify during the encapsulation process, can pose signicant challenges during the manufacture of softgels. Such ll material may be encapsulated into softgels by continuous heating of the material in its reservoir and in the conveying tubing to higher temperatures until it reaches the dosing pump where it is cooled to lower temperatures just before it reaches the wedge for encapsulation.35 Ribbons for Encapsulation During the manufacture of a softgel product using the rotary die process, the gel mass is spread onto the cooling drums to form ribbons with the aid of metering devices known as spreader boxes. A spreader box, as invented by Scherer,36 consists of a hopper having an elongated slot at its bottom and a rotating roll (spindle) spaced between the two edges of the slot to provide a gap through which the molten gel mass is extruded by the rotation of the roll. The mechanism allows the volume of the gel mass passing
through the gap uniform along the entire length of the gap thereby resulting in the formation of a ribbon with uniform thickness across its entire width and length. The thickness of the ribbon can be controlled through controlling the ow of gel mass that can be readily accomplished by increasing or decreasing the speed of the rotating roll. The rotating roll in the hopper mechanism also helps in removing macroscopic air bubbles from the viscous gel mass before it passes through the gap thus enhancing the quality of the lm deposited on the cooling drum. The spreader boxes control the ow of gel mass onto the cooling drums to a ribbon thickness within 10% of set specication. The wet ribbon thickness may vary from 0.022 inches to 0.045 inches, with larger softgel sizes requiring thicker shell to accommodate the higher structural strength required during their manufacture.33 The gel mass is typically at about 57608C when it comes into contact with the cooling drums. The temperature of the cold air used to cool the drums is typically about 13148C.33 The air cooling process may be inefcient in cooling the drums uniformly across their entire surface.37 US patent 7,078,05437 proposes that the surface of the cooling drums and the gelatin sheaths spread over them may be better and more evenly cooled by the cooling drums that use a liquid coolant (e.g., water) than by the ones that use air coolant. The gelatin sheaths containing propylene
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glycol as the plasticizer are substantially tackier than those containing glycerol or sorbitol as the plasticizer and thus difcult to extract from the cooling drums. The use of a liquid coolant in the cooling drums may result in such gelatin sheaths containing propylene glycol sticking less strongly to the cooling drums and thus may be easily removed from them. Another advantage of using a liquid coolant over cold air in cooling the drums is that the cooling process temperature can be altered and controlled more precisely with the former to meet the cooling requirements for various gel mass compositions. For example, the temperature of the coolant water can be altered precisely from about 20228C, optimal operational temperature for a gel mass in the absence of propylene glycol, to about 18208C and 16188C, optimal operational temperatures for gel masses containing 10% and 21% propylene glycol, respectively, as the plasticizer.37 Drying Softgels formed at the encapsulating machine are highly exible due to excessive moisture content of the starting gel mass.34,3841 Softgels originating from the encapsulating machine undergo a primary short time, low intensity drying process followed by a secondary longer time, high intensity drying process. Softgels are initially tumble dried in a hollow drum(s) with perforated walls (Fig. 1B) (primary or rotary drying process).38 Dry air is continuously pumped through the rotating drum(s) at an air temperature lower than 358C. The warm air being blown onto the softgels may penetrate the shell and cause it to dry from the inside by moving the water outward to the surface of the softgel. The warm temperature also helps to keep the gel in semi-uid state that promotes further sealing of softgels. Sometimes adsorbent towels are used in the tumble dryer to remove any lubricant carried over during the encapsulation process. By the time the softgels exit this tumble drying process, a signicant portion of water from the shell has been removed into the ll and/or into the environment. After the softgels exit the tumble dryer (primary or rotary drying process), they are spread on to trays. The nal drying phase (secondary or tray drying process) of the softgels is accomplished by inserting the stacks of trays into a drying tunnel maintained at controlled temperature (21248C) and low relative humidity (2030%) conditions.42 The time for the secondary drying process for softgels may vary from few hours to few days, depending on the nature of the ll formulation (i.e., hydrophilic vs. lipophilic), nature of the shell formulation (e.g., type and concentration of plasticizer(s)), thickness of the shell, and size of the softgels. The shell formulation at the time of encapsulation process
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typically contains water somewhere from 30 to 40% w/w.34,3941 During the encapsulation and subsequent primary drying processes, depending on the nature of the ll formulation encapsulated, the ll may pick up water anywhere from zero percent to 20% w/w. During the secondary drying process, the ll may loose some water leaving an amount anywhere from zero percent to 8% w/w in the ll. The rate and extent of this water migration processes in both directions are inuenced by the nature of the ll formulation, nature of the shell formulation, thickness of the shell, and size of the softgels. The dynamics of water migration during the softgel drying processes is depicted in Figure 2. The moisture content of the ll in a softgel is typically measured using a KarlFisher apparatus. The softgel is cut open at the seam with a knife and the ll is collected into a syringe. The syringe is capped tightly to prevent any moisture transfer between the ll and the surroundings until measurements are completed. The moisture content of the shell is measured using a loss on drying (LOD) apparatus. The softgel is cut open at the seam with a knife and its ll contents are drained. The shell is then given a quick wash in a suitable organic solvent,
Figure 2. Dynamics of Water Migration during Softgel Drying Process Water migration patterns during drying of a softgel product containing a typical (A) PEG 400 ll formulation; (B) mixed medium chain mono-, di-, and triglycerides ll formulation with or without an added surfactant(s); and (C) medium chain triglycerides (MCT) or long chain triglycerides (LCT) ll formulation. Yellow inner core represents ll formulation and brown exterior represents gelatin shell. Numerical values represent approximate percent water content, w/w. ( ) Water migration from shell to ll, ( ) water migration from ll to shell, and ( ) water migration from shell to environment.
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such as petroleum ether, and wiped clean of any remaining ll contents with a paper towel before the measurements are initiated. The hardness of a softgel is measured using a Bareiss hardness tester. Photographs of the Bareiss digital hardness testers are presented in Figure 3. The instrument operates by compressing the softgel under test for a brief period (e.g., 20 s) between a plunger attached to a load cell and a platform which is automatically raised. To test a softgel for its hardness, it is placed horizontally on the platform with its seam contour aligned parallel to the platform and the platform then raised enough so that the softgel is in contact with both the platform and the plunger. During the test, the platform rises automatically and the load cell indicator displays the value of the resistance of the softgel to the compressive force. After the test period, the resistance value is displayed in Newtons (N) and represents the hardness of the softgel under test.41 Drying is a dynamic process and the process continues until the gelatin shell returns to its equilibrium moisture content, which is in the range of 1015% w/w.43 Softgels containing a lipophilic ll generally dry faster than those containing a hydrophilic ll and typically reach equilibrium shell moisture within 24 h. If water migrates into the ll from the shell extensively, more typical of polyethylene glycol lls, it needs to migrate back out until the ll moisture content reaches equilibrium with the moisture content of the shell for the optimal physical stability of a softgel product. The polyethylene glycol based lls may take from 7 to 10 days to reach
Figure 3. Photographs of the Bareiss Hardness Testers A. Analogue hardness tester (Model HP) with the stand (Model BS 61); B. Digital hardness tester (Model HPE II) with the stand (Model BS 61 II). (Courtesy of Heinrich Bareiss Pruefgeraetebau GmbH.) http://www.bareiss.de/english/produkte/pruefgeraete_ start.html.
acceptable moisture levels and may still contain up to 10% water after drying. Softgels permitted to come to moisture equilibrium at the controlled temperature (21248C) and relative humidity (2030%) conditions of the secondary drying process are considered dry.42 The shell material of such dry softgels usually contains 816% w/w water depending on the specic gelatin shell formulation used. The range of water content between 7.6% and 14% in gelatin was hypothesized to correspond to the water sorbed by the polar groups in gelatin or the structural water, which is bound with the proteins by hydrogen bonding both inside and outside the helical fragments.44,45 The ll material of the dry softgels usually contains as high as 610% w/w water for a simple polyethylene glycol 400 based formulation to less than 0.5% w/w water for a medium chain triglyceride (MCT) or a long chain triglyceride (LCT) oil based formulation (Fig. 2). After the softgels are dry, they may be subjected to an additional step, known as stress relieving step or tempering step, to improve the overall quality of a softgel product.42 The step involves a change in the conditions of temperature and relative humidity from the secondary drying step and is accomplished at a temperature range of 32388C and a relative humidity range of 3560%. The stress relieving step can take place in the same tunnel as the secondary drying step, and thus requires no additional equipment or labor. The step is intended to remove any dimples present in the shell and any bubbles present in the ll. In addition, the step also reduces the dimensional standard deviation thereby resulting in more dimensionally uniform batches of softgels.42 The dimensional uniformity of a softgel product is typically measured by the standard deviation in the lengthwise and widthwise measurement of an oblong softgel or the diameter wise of a round softgel. The rate and extent of softgel drying are the critical processing parameters that should be carefully controlled. Removal of too much water may result in hard, brittle softgels that have a higher propensity to develop cracked shells and/or require a longer time for dissolution. On the other hand, insufcient drying may result in very soft softgels that become tacky and/ or tightly stick to each other with time. If the softgels are subjected to rapid drying conditions, such as high drying temperature, very low relative humidity, and/ or high airow, the product may under go a phenomenon referred to as case hardening.46 Case hardening occurs when the exterior surface of the softgel dries very rapidly and forms a temporary seal that prevents further egress of moisture from the ll and shell. The hardness of such a softgel increases temporarily reaching an acceptable value. However, the excess moisture entrapped within the ll and shell migrates slowly during storage, resulting in a
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very soft softgel product. An acceleration of the drying process can also potentially lead to considerable changes in the structure and properties of the shell material. Though the presence of a plasticizer in the shell formulation may mitigate these deleterious effects of the faster drying conditions to some extent, the drying process should be carefully controlled to minimize its effects on the thermal and mechanical properties of the shell material.47 Finishing After drying, the softgels are sorted (sized),48 polished, printed,49 and inspected for their quality. The softgels are then packaged into suitable containers, typically of low density polyethylene (LDPE) bags, high density polyethylene (HDPE) bottles, or blisters. The recommended storage conditions for the softgels include a temperature range of 15308C and a relative humidity of not more than 50%.43,50 When stored under these conditions, the equilibrium moisture content of the shell material and oxygen permeability through the material are minimal, thus improving the stability of the softgel product.43 The readers are directed to the review by Wilkinson and Hom51 to obtain an extensive understanding of the design of a softgel manufacturing facility and equipment used in the softgel manufacturing.
promising in improving its bioavailability. A vehicle for the development of a softgel ll formulation should ideally satisfy the following criteria: Pharmaceutically acceptable for oral use. Sufcient solubilizing capacity to dissolve a given dose in a small volume. Yield a ll formulation that is stable and compatible with gelatin shell material. Yield a ll formulation that is easier to compound and encapsulate. Prevent precipitation of the solubilized compound within the softgel product during its manufacturing and shelf-life, and upon contact with the aqueous environment in vitro (dissolution) and in vivo (GIT). Vehicles suitable for encapsulation into softgels can be broadly classied into two groups: A. Hydrophilic vehicles. B. Lipophilic vehicles (lipid based ll formulations). Hydrophilic Vehicles Hydrophilic vehicles for softgel ll formulations include polyethylene glycols (e.g., PEG 400, PEG 600), methoxypolyethylene glycols (e.g., MPEG 350, MPEG 550), diethyleneglycol monoethyl ether (Transcutol1), tetrahydrofurfurylalcohol polyethylene glycol (Glycofurol), propylene carbonate, Nmethyl-2-pyrrolidone (NMP), polyoxyethylenepolyoxypropylene copolymers (Poloxamers), propylene glycol, glycerin, ethyl alcohol, and water. The use of propylene glycol, glycerin, and water is restricted to less than 10% of the total ll formulation, as these vehicles can also act as plasticizers for the gelatin shell.54 Similarly, use of lower molecular weight polyethylene glycols (e.g., PEG 200, PEG 300) in the ll formulations is limited due to their ability to diffuse into the shell and thereby act as gelatin plasticizers.5557 The extent of diffusion of a polyethylene glycol from the ll into the shell decreases with an increase in its molecular weight.40,41 The use of volatile components, such as ethyl alcohol, in the ll formulations is limited due to their ability to rapidly diffuse through the shell material, and carrying out other ll components in the process.54,5860 Pros and Cons of Use of Polyethylene Glycols in Softgels Polyethylene glycols, due to their ability to be miscible with aqueous uids in all proportions and dissolve many pharmaceutical compounds at the same time make them ideal vehicles for the delivery of many poorly soluble compounds in softgels. Compounds with poor bioavailability and considerable
FILL FORMULATIONS
Types of ll formulations that can be delivered using softgel delivery system include: solutions, suspensions, emulsions, microemulsions, self-emulsifying drug delivery systems (SEDDS), and self-microemulsifying drug delivery systems (SMEDDS). The consistency of a ll formulation may vary from a free owing liquid (e.g., Rocaltrol1 Softgels, Roche Pharmaceuticals; Hectorol1 Softgels, Genzyme Corporation) to a thick suspension (e.g., Zantac1 Softgels, GlaxoSmithKline; Prometrium1 Softgels, Solvay Pharmaceuticals). In the case of self-microemulsifying (SMEDDS) and self-emulsifying (SEDDS) formulations, a compound dissolved in a lipophilic vehicle containing one or more emulsiers and cosolvents, forms a microemulsion (droplet size 0.15 mm) when the ratio of emulsier to lipid is high (>1) or a ne emulsion (droplet size >0.15 mm) when the ratio is <1, respectively, upon dilution with aqueous uids in vitro or in vivo.52 Compounds belonging to class II and class IV of the Biopharmaceutics Classication System (BCS) show extremely low aqueous solubility throughout the physiological pH range, resulting in low and inconsistent bioavailability.53 However, when such a compound demonstrates enhanced solubility in a nonaqueous vehicle, softgel delivery system may be
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individual variability in the absorption have been shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in polyethylene glycols.6167 However, while polyethylene glycols often may have high solubilizing power for some poorly water soluble compounds, the high afnity of these vehicles for water can potentially lead to the precipitation of dissolved compounds when the formulation comes into contact with an aqueous environment in vitro or in vivo.6872 The solvent capacity of a hydrophilic solvent, such as polyethylene glycol and propylene glycol, for a hydrophobic compound has been shown to fall approximately logarithmically as the formulation is diluted with water.69,71 Serajuddin et al.,69 for example, demonstrated a sharp reduction in the solubility of a test compound in PEG 400 from 250 mg/ g to about 1.5 mg/g with an increase in water content from 0% to 50% in the formulation (Fig. 4). Gross crystallization of the solubilized test compound was also observed when the PEG 400 based solution formulation was encapsulated into softgels, due to the migration of water from the shell into the ll. This water-prone crystallization process may result in the improvements in the bioavailability of a compound a dose-dependent phenomenon, that is, higher percent bioavailability at lower doses and diminished percent bioavailability as the dose increases.70,72 For example, the oral bioavailability of a poorly soluble investigational compound, DMP 323 (aqueous
solubility 10 mg/mL), from PEG 400 solution was shown to diminish in fasted beagle dogs from 49.6 19.7% to 5.2 1.8% when the dose was increased from 100 to 350 mg.70 The reduced bioavailability of the compound from PEG 400 solution at the higher dose was attributed to the extent of its precipitation in the aqueous uids of the GIT. A blend of two or more of polyethylene glycols of various molecular weights may sometimes be used either to modify the consistency of a ll formulation and thereby prevent settling of material in a suspension formulation66 or to control the rate of release of an encapsulated compound from a softgel product.73 Such a formulation can be easily compounded at a temperature slightly higher than the melting point of the higher molecular weight polyethylene glycol used in the blend and then brought to a semisolid form by lowering the temperature during its encapsulation. The formulation remains solidied in the softgel at ambient temperature and thereby minimize the settling and migration of any of the ll components. Such a semisolid ll formulation may also have an added advantage of providing effective deterrent to potential intravenous drug abuse on account of its high viscosity making injection at ambient temperature difcult.66 The rate of release or the potential for drug abuse of an encapsulated compound from such a semisolid matrix may be further controlled by including a gelling agent, such as an organic polymeric material (e.g., cellulose polymers, acrylic acid polymers)73,74 or an inorganic salt (e.g., calcium acetate)75 in the formulation. Absorption of Polyethylene Glycols Orally administered polyethylene glycols of a lower molecular weight (e.g., PEG 200, PEG 300, PEG 400) are well absorbed in the GIT and are mostly (>90%) excreted unchanged in urine and feces in human subjects.76 Absorption studies in human volunteers have shown that about one-third of the orally administered PEG 400 is excreted in the urine and the remainder of the dose is likely to pass through the gut intact and subsequently eliminated in the feces.77,78 In addition, more than 75% of PEG 400 found in the urine is excreted within the rst 4 h after oral administration, implying that absorption of the polymer predominantly occurs from the small intestine.78 Lower molecular weight polyethylene glycols are hypothesized to be absorbed through the intestinal epithelium by passive diffusion and solvent drag.79 The oral absorption of a polyethylene glycol has been shown to decrease with an increase in its molecular weight (e.g., fraction absorbed: 100% for PEG 200 and PEG 300, 10% for PEG 4000, 0% for PEG 6000).8084
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Figure 4. Inuence of Added Water on the Solubility of Poorly Soluble a-pentyl-3-(2-quinolinylmethoxy) benzene methanol in PEG 400 at 208C (Insert-Semilogarithmic Plot) (Adopted from Serajuddin et al.69).
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Inuence of PEG 400 on GIT Motility and Absorption of Compounds Mechanistically, PEG 400 was shown to have a concentration-dependent effect on gastrointestinal motility and transit.78,85,86 Radiolabeled studies have suggested that the mean gastric residence time (MGRT) of an aqueous vehicle containing PEG 400 was similar to that of an aqueous vehicle free from PEG 400 (MGRT of about 20 min). The mean small intestinal transit time (MSITT), in contrast, was shown to decrease with an increase in the concentration of PEG 400 in the aqueous vehicle (MSITT of 153 min at 10 g PEG 400 dose in aqueous vehicle versus 236 min for PEG 400 free aqueous vehicle).85 The mechanism behind the inuence of PEG 400 on the intestinal transit of a coadministered liquid formulation was attributed to the incomplete absorption of the polymer from the intestine and the resulting polymer induced osmotic activity. PEG 400 would probably increase the luminal uid volume via the retention of water, which in turn stimulates intestinal motility and hence transit.87 Since the small intestine is the primary site for absorption of many compounds, a reduction in the contact time with this region of the GIT could potentially impact the bioavailability of orally administered compounds. The absorption of low permeability compounds (i.e., BCS class III and class IV) is likely to be the most susceptible to changes in intestinal residence time.88 PEG 400 at higher levels (!2.5 g), for example, was shown to reduce the small intestinal residence time of a liquid formulation, resulting in a signicant reduction in the oral bioavailability of ranitidine, dissolved within.78,85,86 However, at a lower concentration (1 g), PEG 400 was shown to signicantly enhance the absorption of ranitidine, possibly via modulation of intestinal permeability.86 PEG 400 was also thought to have a signicant impact on efux process via P-gp transporter inhibition and metabolism of some drugs during their migration through the GIT.89 Solubility Enhancers for Hydrophilic Vehicles It is desirable to produce a highly concentrated solution of a compound as it allows the encapsulation of a unit dose of the compound in a softgel that is small enough to swallow easily and thus improving patient acceptance of the medication. Yu et al.,90 Morton et al.,91 and Shelley et al.92 invented methods for enhancing the solubility and producing highly concentrated solutions for acidic, basic, and amphoteric compounds in hydrophilic vehicles suitable for lling softgels (referred to as enhanced solubility system or ESS).93 These inventions allow the improvement in the solubility of some compounds in polyethylene glycols by 40400% using an ionizing
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agent (i.e., counter-ion; neutralizing agent). For example, the solubility of acidic compounds (e.g., ibuprofen, naproxen, indomethacin, acetaminophen) in polyethylene glycols can be enhanced through partial ionization of these compounds with a hydroxide ion species (e.g., sodium hydroxide, potassium hydroxide, ammonium hydroxide). Whereas, the solubility of basic compounds (e.g., thioridazine, cimetidine, ranitidine, nifedipine) can be enhanced through partial ionization with a hydronium ion species (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, an organic acid). For amphoteric compounds, either hydroxide ion or hydronium ion sources may be utilized to effect enhanced solubilization. The solubility enhancing techniques employed by Yu et al.,90 Morton et al.,91 and Shelley et al.92 result in a softgel ll formulation containing a compound as a mixture of its unionized form (free acid or base) and its corresponding ionized form (i.e., salt form). When used these neutralization (counter ion) techniques to obtain a highly concentrated solution of a compound, it is essential to keep the apparent pH of the nal ll formulation at least between 2.5 and 7.5. At pH values below 2.5, gelatin is hydrolyzed94 causing leakage of the softgel, whereas at pH values above 7.5, gelatin may be either hydrolyzed94 or tanned (i.e., cross-linked) resulting in decreased solubility of the gelatin shell.33 In addition, the ionizing agents used as solubility enhancers contain a highly reactive species which may react adversely with other ingredients present in the softgel.95 The use of a highly reactive species, such as hydroxide ion, may be substituted with a milder and relatively neutral salt, such as ammonium acetate,96 an alkali metal acetate,92 or a combination of alkali metal acetate/lactate,97 in enhancing the solubility of acidic compounds that is more compatible with the other softgel components. Alternately, the solubility of some compounds (e.g., acetaminophen, danazol, ibuprofen) in hydrophilic vehicles can also be improved signicantly by using povidone (polyvinylpyrrolidone, PVP) as a solubility enhancer.55,56,67,98 Unlike the solubility enhancing techniques employed by Yu et al.,90 Morton et al.,91 and Shelley et al.,92 the use of povidone as a solubility enhancer results in a softgel ll formulation containing a compound in its original form that is very compatible with the other softgel components. In addition, as povidone is available in a variety of molecular weights ranging from 2500 to 3000000,99 the viscosity of a ll formulation can be controlled through the selection of appropriate molecular weight and concentration of the polymer without adversely affecting the solubility of dissolved compounds.98 An advantage of using a higher amount of a lower molecular weight povidone as a
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solubility enhancer is the reduction in the amount polyethylene glycol available in the ll formulation for any potential reactions with acidic compounds such as ibuprofen free acid (e.g., esterication reactions), a well known disadvantage that results in the reduction of available ibuprofen in its free form.100 Use of povidone of a lower molecular weight also yields a ll formulation of a lower viscosity and thus improving the product manufacturability and dissolution characteristics.98 Lipophilic Vehicles (Lipid Based Fill Formulations) Lipophilic vehicles for softgel ll formulations include free fatty acids (e.g., oleic acid), fatty acid esters of hydroxyl compounds, such as ethyl alcohol, propylene glycol, glycerin, sorbitol, sucrose, polyethylene glycols, and polyethoxylated fatty acid esters. The fatty acid composition of these esters may vary from short chain (SC, <C8) to medium chain (MC, C8-C10) to long chain (LC, !C12). Classication of Lipid Based Fill Formulations Lipid based ll formulations generally comprise of a compound dissolved or suspended in one or more excipients consisting of triglycerides (TG), mixed glycerides, surfactants, and cosolvents. The simplest lipid formulation is one in which a compound is dissolved in a digestible oil, usually a long chain triglyceride (LCT, e.g., vegetable oil) or a medium chain triglyceride (MCT, e.g., fractionated coconut oil). These formulations may be appropriate for potent compounds and/or highly lipophilic compounds (log P > 4) and require digestion of the formulation before absorption.71,101,102 Some compounds may have limited solubility in triglycerides or may yield lower bioavailability when dosed in these formulations.103,104 The solvent capacity of triglyceride vehicles for some compounds may be improved by blending them with other mixed glycerides, that is, diglycerides (DG) and monoglycerides (MG), and free fatty acids (FA). The advantage of using these mixed glycerides is that these components are similar to the natural digestion products of the triglycerides and do not interfere with the regular lipid digestion and absorption processes. These triglyceride and mixed glycerides formulations are referred to as type I under lipid formulation classication system (LFCS), proposed by Pouton71,101,102 and Porter et al.105 The solubilization of a compound in a type I lipid formulation may sometimes be improved with the inclusion of a lipophilic surfactant (HLB < 12). This approach is used primarily to promote the emulsication of a formulation vehicle in the aqueous uids of the GIT under gentle agitation. This type of lipid formulation is likely to retain its solvent capacity for the
dissolved compound after dispersion in the aqueous uids. These formulations are referred to as type II under LFCS. In contrast, a type I lipid formulation may include a hydrophilic surfactant (HLB > 12) and/or a water soluble cosolvent (e.g., propylene glycol, polyethylene glycol, ethyl alcohol) to increase the solvent capacity of the formulation for a compound. These formulations are referred to as type III under LFCS. A type IV formulation comprises predominantly of a hydrophilic cosolvent and a surfactant, and with or without minimal oil components. The digestion (lipolysis) of a triglyceride within the GIT by the pancreatic lipase/colipase complex into amphiphilic diglycerides, monoglycerides, and free fatty acids can enhance the dissolution rate of a poorly soluble compound coadministered with the vehicle (the subject will be discussed in more detail in Lipid Digestion and Absorption and Inuence on Absorption of Compounds Section). However, the poor miscibility of the undigested triglyceride with the GIT aqueous environment may lead to highly variable gastric emptying and/or dispersion into an emulsion which in turn, can result in variable absorption of the compound from the GIT.106 The dispersibility of the triglyceride in the GIT uids can be enhanced by including a surfactant in the formulation. Interestingly, Lacy et al.,107 using in vitro digestion experiments, demonstrated that the lipolysis of a triglyceride might be retarded by a hydrophilic surfactant (i.e., HLB >10) (e.g., Cremophor RH 40, Cremophor EL, Polyoxyethylene sorbitan monooleate), typically used in the lipid based ll formulation for a poorly soluble compound (type III formulation). Lacy et al.107 further demonstrated that the inhibitory effect of a hydrophilic surfactant on the in vitro lipolysis of a triglyceride could be countered substantially by the inclusion of a lipophilic surfactant (i.e., HLB < 10) in the formulation. Some examples of such benecial lipophilic surfactants include, free fatty acids (e.g., oleic acid, linoleic acid, linolenic acid), mono- and/or di-glycerides (e.g., glyceryl mono- and di-caprylate/caprate, distilled acetylated monoglycerides), sorbitan fatty acid esters (e.g., sorbitan monolaurate, sorbitan monooleate), and polyglycerol esters of fatty acids (e.g., polyglyceryl oleate). Few examples of currently marketed lipid based formulations delivered using softgel technology are included in Table 2. The list includes such well known products as Cyclosporine A (Sandimmune1 [type II] and Neoral1 [type III]; Novartis Pharmaceuticals, Australia), Ritonavir (Norvir1; Abbott Laboratories), Lopinavir/Ritonavir (Kaletra1; Abbott Laboratories), Saquinavir (Fortovase1; Roche Pharmaceuticals), Amprenavir (Agenerase1 [type IV]; GlaxoSmithKline), Calcitriol (Rocaltrol1 [type I];
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Table 2. Examples of Softgel Products with Their Fill Compositions and Dissolution Methods
Drug Product Information Hydrophilic lls Agenerase1, Amprenavir, 50 and 150 mg, GlaxoSmithKline, NDA 21-007 Fill Excipients PEG 400, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), propylene glycol Properties, Dissolution Method HIV-protease inhibitor, MW 505.63, Aq. Sol. 40 mg/mL, clog P 3.29306, BCS Class II307 Softgel-introductory dosage form. Amprenavir softgel product was later reformulated into a tablet formulation (Lexiva1, NDA 21-548) containing its phosphate ester prodrug, fosamprenavir calcium, with improved aqueous solubility Apparatus I at 50 rpm in 900 mL of 0.1 N HCl at 37 0.58Ca Antineoplastic, MW 348.48, Aq. Sol. insoluble Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of 0.05 M phosphate buffer, pH 7.5 containing 0.5% hexadecyltrimethylammonium bromide (HDTMA) at 37 0.58Ca Heart failure, cardiotonic, MW 780.94, Aq. Sol. 10 mg/mL, BCS Class I308,309 More complete absorption of digoxin from soft capsules and recommended oral doses are only 80% of those for tablets and elixir Apparatus I at 120 rpm in 600 mL of water (37 0.58C)b Anticonvulsant, MW 141.17, Aq. Sol. freely soluble Softgel-introductory dosage form Apparatus I at 50 rpm in 900 mL of phosphate buffer, pH 6.8 at 37 0.0.58Cc Antineoplastic, MW 588.56, Aq. Sol. 0.20 mg/mL310 Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of acetate buffer, pH 4.5 at 37 0.0.58Cc Anti-inammatory MW 206.28, Aq. Sol. 10 mg/mL, BCS Class II308,309 Initial launch as tablet (NDA 18-989); softgel as line-extension Apparatus I at 150 rpm in 900 mL of phosphate buffer, pH 7.2 at 37 0.0.58Ca
Targretin1, Bexarotene, 75 mg, Eisai/Ligand, NDA 21-055
PEG 400, polysorbate 20, povidone K-90, butylated hydroxyanisole (BHA)
Lanoxicap1, Digoxin, 0.05, 0.1, and 0.2 mg, GlaxoSmithKline, NDA 18-118
PEG 400, ethyl alcohol, propylene glycol
Zarontin1, Ethosuximide, 250 mg, Pzer, NDA 12-380
PEG 400
VePesid1, Etoposide, 50 mg, Bristol-Myers-Squibb, NDA 19-557
PEG 400, glycerin, water, citric acid
Advil1, ibuprofen, 200 mg, Wyeth, NDA 20-402
PEG 600, potassium hydroxide, water, (ibuprofen is present as free acid/potassium salt)
Ibuprofen Capsules, Ibuprofen, 200 mg, Banner Pharmacaps, Inc., NDA 21-472 Advil PM Liqui-Gels1, Ibuprofen 200 mg and, Diphenhydramine HCl 25 mg, Wyeth, NDA 21-393
PEG 600, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), povidone, (ibuprofen is present as free acid) PEG 600, potassium hydroxide, water, (ibuprofen is present as free acid/potassium salt)
Aleve1, Naproxen sodium, 220 mg, Bayer HealthCare, NDA 21-920
PEG 400, propylene glycol, povidone, lactic acid
Anti-inammatory/antihistaminic, sedative, hypnotic, MW 206.28 and 291.82, Aq. Sol. 10 mg/mL and 1 g/mL, BCS Class II308,309 Apparatus I at 100 rpm in 900 mL of 200 mM phosphate buffer, pH 7.2 at 37 0.58Ca Anti-inammatory, MW 252.24, soluble (Continued)
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Table 2. (Continued )
Drug Product Information Fill Excipients Properties, Dissolution Method Initial launch as tablet (NDA 17-581; as free acid); softgel as second-line Apparatus II at 50 rpm in 900 mL of 0.1 M phosphate buffer (pH 7.4), at 37 0.58Cd Antianginal, MW 346.33, Aq. Sol. 12 mg/mL, BCS Class II308,309,311 Softgel-introductory dosage form, tablet as line-extension (NDA 19-684; higher doses) Apparatus II at 50 rpm in 900 mL of SGF at 37 0.58Cc Vasodilator, MW 418.44, Aq. Sol. 4 mg/mL, BCS Class II312 Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of water, containing 0.5% sodium dodecyl sulfate at 37 0.58Ca Benign prostatic hyperplasia (BPH), MW 459.92, Aq. Sol. 24.2 mg/mL Initial launch as tablet (NDA 19-057); softgel as line-extension NSCLC, breast cancer, multiple myeloma, MW 1079.11, Aq. Sol. >1000 mg/mL Renal osteodystrophy, hyperparathyroidism, hypocalcaemia, rickets, MW 400.64, Aq. Sol. insoluble Calcium regulator, MW 416.64, Aq. Sol. insoluble Softgel-introductory dosage form USP rupture testd Antihyperparathyroidism, MW 412.65, Aq. Sol. insoluble Softgel-introductory dosage form USP rupture testd Anorexia, nausea, MW 314.46, log P 3.78 Softgel-introductory dosage form Apparatus II at 100/150 rpm in 500 mL of water, containing 10% Labrasol (37 0.58C)a. Plus USP rupture test,c,d Benign prostatic hyperplasia (BPH), MW 528.53, Aq. Sol.<0.038 ng/mL, log P 5.09 Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of 0.1 N HCl containing 2% sodium dodecyl sulfate at 37 0.58Ca Parathyroid disease, refractory rickets, MW 396.65, Aq. Sol. insoluble Softgel-introductory dosage form USP disintegration testc Antihistamine, MW 382.88, Aq. Sol. insoluble Initial launch as tablet (NDA 19-658); softgel as line-extension (Continued)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010 DOI 10.1002/jps
Procardia1, Nifedipine, 10 and 20 mg, Pzer, NDA 18-482
PEG 400, glycerin, peppermint oil, sodium saccharin
Nimotop1, Nimodipine, 30 mg, Bayer HealthCare, NDA 18-869
PEG 400, glycerin, peppermint oil, water
Hytrin1, Terazosin HCl, 1, 2, 5, and 10 mg, Abbott Laboratories, NDA 20-347 Navelbine1, Vinorelbine tartrate, 20, 30, and 80 mg, Pierre Fabre, NDA 20-388 Lipophilic solution lls One Alpha1, Alfacalcidol, 0.25 mg, 0.5 mg, and 1 mg, LEO Pharma, Ex-US Rocaltrol1, Calcitriol, 0.25 mg and 0.5 mg, Roche Pharmaceuticals, NDA 18-044 Hectorol1, Doxercalciferol, 0.5, 1, and 2.5 mg, Bone Care Int., Inc., NDA 20-862 Marinol1, Dronabinol, 2.5, 5, and 10 mg, Unimed and Roxane, NDA 18-651
PEG 400, glycerin, povidone
PEG 400, ethanol, glycerol, water
Sesame oil, dl-alpha-tocopherol
Fractionated coconut oil, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) Fractionated coconut oil, ethyl alcohol, butylated hydroxyanisole (BHA)
Sesame oil
Avodart1, Dutasteride, 0.5 mg, GlaxoSmithKline, NDA 21-319
Medium chain mono- and diglycerides, butylated hydroxytoluene (BHT)
Drisdol1, Ergocalciferol, 50000 IU, Sano-Aventis, NDA 3-444
Soybean oil
Claritin1, Loratadine, 10 mg, Schering-Plough, NDA 21-952
Caprylic/capric glycerides, polysorbate 80, povidone
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Drug Product Information Amitiza , Lubiprostone, 24 mg, Sucampo and Takeda, NDA 21-908 Zemplar1, Paricalcitol, 1, 2, and 4 mg, Abbott Laboratories, NDA 21-606 Fortovase1, Saquinavir, 200 mg, Roche Pharmaceuticals, NDA 20-828
1
Fill Excipients Medium chain triglycerides
Properties, Dissolution Method Chronic idiopathic constipation, MW 390.46, Aq. Sol. insoluble Softgel-introductory dosage form Antihyperparathyroidism, MW 416.64, Aq. Sol. insoluble, BCS Class IV Softgel-introductory dosage form HIV-protease inhibitor, MW 670.84, Aq. Sol. 2.2 mg/mL, log P 2.73, clog P 4.73, BCS Class IV305307 Fortovase1 softgel product was replaced with tablet (Invirase1 500 mg) and powder lled HGC capsule (Invirase1 200 mg) formulations containing its mesylate salt, with reduced dosing (NDA 21-785 and NDA 20-628) Apparatus II at 50 rpm in 900 mL of citrate buffer containing 0.582% anhydrous dibasic sodium phosphate and 1.67 g citric acid monohydrate at 37 0.58Cc Hypogonadism, MW 456.70, Aq. Sol. insoluble Antiepileptic, MW 144.21, Aq. Sol. 1.3 mg/mL, BCS Class II309 Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of SIF TS without enzyme and with monobasic sodium phosphate (instead of monobasic potassium phosphate) and pH adjusted to 7.5 with 5 M sodium hydroxide; containing 0.5% sodium dodecyl sulfate at 37 0.58Cc Atopic dermatitis, MW 300.44, Aq. Sol. insoluble
Medium chain triglycerides, ethyl alcohol, butylated hydroxytoluene (BHT) Medium chain mono- and diglycerides, povidone, DL-a-tocopherol
Andriol1, Testosterone undecanoate, 40 mg, Organon, EX-US Depakene1, Valproic acid, 250 mg, Abbott Laboratories, NDA 18-081
Castor oil, propylene glycol monolaurate Corn oil
Lipophilic suspension lls Toctino1, Alitretinoin, 10 and 30 mg, Basilea Pharmaceutica AG, Ex-US Symmetrel1, Amantadine HCl, 100 mg, Novartis Pharmaceuticals, Ex-US Lamprene1, Clofazimine, 50 and 100 mg, Novartis Pharmaceuticals, NDA 19-500
Accutane1, Isotretinoin, 10, 20, and 40 mg, Roche Pharmaceuticals, NDA 18-662
Rened soya-bean oil, partially hydrogenated soya-bean oil, medium chain triglycerides, yellow beeswax, All-rac-a-tocopherol Rape seed oil, soybean lecithin, blend white beeswax and hydrogenated soya and vegetable oils Rapeseed oil, hydrogenated soybean oil, partially hydrogenated vegetable oils, propylene glycol, beeswax, butylated hydroxytoluene (BHT), soybean lecithin, p-methoxy acetophenone, sodium ethyl paraben, sodium propyl paraben Soybean oil, beeswax, hydrogenated soybean oil akes, hydrogenated vegetable oil, butylated hydroxyanisole (BHA), edetate disodium
Infections, inuenza, Parkinsons, MW 187.71, Aq. Sol. freely soluble Antileprosy, MW 473.40, Aq. Sol. 0.49 mg/mL, log P 4.36, BCS Class II/IV307,313 Softgel-introductory dosage form USP rupture testd Antiachne, MW 300.44, log P 6.6117 Softgel-introductory dosage form Apparatus I at 100 rpm in 900 mL of 0.05 M potassium phosphate dibasic buffer, pH 7.8 containing 0.5% lauryldimethylamine-oxide (LDAO) at 37 0.58Ca
(Continued)
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Drug Product Information Glakay , Menatetrenone, 15 mg, Eisai Co., Ex-US
1
Fill Excipients acid, carnauba wax, hydrogenated oil, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol esters of fatty acids, glyceryl monooleate Peanut oil, lecithin
L-Aspartic
Properties, Dissolution Method Osteoporosis, MW 444.65, Aq. Sol. insoluble
Prometrium1, Progesterone, 100 and 200 mg, Solvay/Schering, NDA 19-781
Hormone, MW 314.46, Aq. Sol. insoluble, log P 3.78305 Softgel-introductory dosage form USP rupture testd Treatment of ulcers, MW 350.86, Aq. Sol. soluble Withdrawn from market Apparatus II at 50 rpm in 900 mL of water at 37 0.58C
Zantac1, Ranitidine HCl, 150 and 300 mg, GlaxoSmithKline, NDA 20-095
Medium chain triglycerides, mixed glycerides of long chain fatty acids (Gelucire1 33/01)
Self-emulsifying (SEDDS) and self-microemulsifying (SMEDDS) lls Sandimmune1, Cyclosporin A, 25, 50, and 100 mg, Novartis Pharmaceuticals, NDA 50-625 Neoral1, Cyclosporin A, 25 and 100 mg, Novartis Pharmaceuticals, NDA 50-715
Corn oil, ethyl alcohol, linoleoyl macrogolglycerides Corn oil-mono- and di-triglycerides, ethyl alcohol, polyoxyl 40 hydrogenated-castor oil, propylene glycol, DL-a-tocopherol
Immunosuppressant MW 1202.61, Aq. Sol. 40 mg/mL, LogP 2.92, BCS Class IV305,314,315 Apparatus II at 75 rpm in 500 mL (for 25 mg dose) or 1000 mL (for 100 mg dose) of 0.1 N HCl containing 2 mg/ mL (for 25 mg dose) or 4 mg/mL (for 100 mg dose) of N,N-dimethydodecylamine N-oxide at 37 0.58Ca, plus USP rupture test,c,d
Cyclosporine Capsules, Cyclosporin A, 25 and 100 mg, Eon Labs Mfg., Inc., ANDA 65-017 Kaletra1, Lopinavir 133.3 mg, Ritonavir 33.3 mg, Abbott Laboratories, NDA 21-226
PEG 400, ethyl alcohol, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), polyoxyl 40 hydrogenatedcastor oil Oleic acid, polyoxyl 35 castor oil, propylene glycol
Norvir1, Ritonavir, 100 mg, Abbott Laboratories, NDA 20-659
Oleic acid, ethyl alcohol, polyoxyl 35 castor oil, butylated hydroxytoluene (BHT)
HIV-protease inhibitor, lopinavir-MW 628.80, Aq. Sol. 40 mg/mL, clog P 6.09, BCS Class IV306,307,316 Softgel-introductory dosage form Kaletra1 softgel product was replaced with a tablet formulation with increased drug loading (strength 200 mg/50 mg) and with reduced food effects (NDA 21-906) Apparatus II at 50 rpm in 900 mL of 10 mM sodium phosphate monobasic solution containing 0.05 M polyoxyethylene 10 lauryl ether, pH 6.8 at 37 0.58Ca HIV-protease inhibitor MW 720.94, Aq. Sol. 1 mg/mL, clog P 4.94, BCS Class IV306,309,311 Softgel-introductory dosage form Apparatus II at 50 rpm in 900 mL of 0.1 N HCl, containing 0.025 M polyoxyethylene 10 lauryl ether at 37 0.58Ca
Information on ll excipients was collected from label, prescription information, or available FDA approval packages; information on indication, molecular weight (MW), and aqueous solubility was collected from The Merck Index, 2006 or otherwise referenced. a FDA Website http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?PrintAll1. b British Pharmacopeia, 1998. c USP/NF Monographs. d US Pharmacopeia, 2009.
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Roche Pharmaceuticals), and Isotretinoin (Accutane1; Roche Pharmaceuticals).
Lipid Digestion and Absorption and Inuence on Absorption of Compounds The consumption of a meal, particularly one containing a large quantity of lipids, stimulates a number of physiological responses, including a reduction in gastric transit (with no change in small intestinal transit108), alterations in gastric pH, secretion of pancreatic enzymes, stimulation of biliary lipid release from the gallbladder, and promotion of lymphatic transport.109111 The resultant release of biliary lipids, primarily bile salts, phospholipids, and cholesterol, promotes the formation of a number of colloidal species in association with the digestion (lipolysis) products from the triglyceride (e.g., diglycerides, monoglycerides, and fatty acids) within the small intestine.112,113 A prerequisite to the lipid absorption process is the micellar diffusion of these lipid digestion products across the aqueous boundary layer and then into the microclimate adjacent to the intestinal membrane. Once in the enterocytes, fatty acids and monoglycerides of carbon chain length more than 12 are combined with phospholipids/cholesterol to form triglyceride, which packs into chylomicrons (0.050.75 mm) and enter the lymph system. Chylomicrons are the major lipid transporting lipoproteins in intestinal lymph and are composed primarily of a triglyceride core which is stabilized in the aqueous environment of the lymph by a surface coating of phospholipids, cholesterol, and proteins.114 The phospholipids in chylomicrons are mainly of endogenous origin, the cholesterol derives from many sources (diet, blood, digestive secretions, newly synthesized in the enterocytes), and the triglycerides contain both endogenous and exogenous fatty acids.114,115 The lymphatic transport of a lipophilic compound, via chylomicrons, may eventually be determined by its solubility and partitioning into the triglyceride core of the chylomicrons.116 Lipophilic compounds with (a) a high log P (>5), (b) signicant solubility in LCT (!50 mg/mL), and (c) administered either in fed state or with an appropriate lipid source in fasted state, are thought to potentially gain direct access to the systemic circulation through the intestinal lymphatic transport, resulting in the improved bioavailability of these compounds.116121 Compounds transported from the intestinal lumen by the intestinal lymph gain access to the general circulation of the body at the junction of the left internal jugular and left subclavian veins, thereby bypassing the hepatic system.116 Food intake, due to its affect on reduced gastric transit, can increase the solubilization time and thus the solubility of a poorly soluble compound in the stomach contents.108 The formation of the aforementioned mentioned colloidal species further aids in the solubilization of poorly soluble compounds in the GIT,
Characteristics of Lipid Based Fill Formulations A type II formulation yields a broader particle size distribution in micron size upon aqueous dilution (SEDDS), whereas a type III formulation yields a clear or almost clear dispersion with micron (SEDDS) or submicron (SMEDDS) size distribution. A distinction between type III and type II lipid formulations is that the water soluble components in the former formulation will tend to part from the oil during dispersion and become dissolved in the aqueous phase. Pouton71 speculated that the forces involved in this phase separation may be the driving force for the emulsication of a type III formulation and coined the phrase diffusion and stranding to describe the process. In contrast, the lipophilic surfactant in a type II formulation would less likely disperse extensively into the aqueous phase and promote the emulsication of glycerides in the aqueous phase. The unfavorable consequence of type III and also type IV formulations is that the dissolved compound may be partially or completely precipitated when these formulations come in to contact with an aqueous environment in vitro or in vivo.70,103 The extent of precipitation of a dissolved compound from these formulations will ultimately depend on the aqueous solubility of the compound and hydrophilicity of the lipid formulation. Compounding the problem further, the precipitated compound can take on a variety of forms including the amorphous form, crystalline form, and of varying particle size distributions depending upon the nature of the aqueous environment and the kinetic conditions that exist in the GIT.24 It is essential to evaluate these properties in vitro during the selection of a softgel ll vehicle as they could potentially impact the in vivo bioavailability of a solubilized compound. For example, the oral bioavailability of a poorly soluble investigational compound, WIN 54954, in fasted beagle dogs was shown to be erratic and inconsistent when it was administered as a solution in PEG 600-Polysorbate 80 solvent blend (type IV formulation).103 In contrast, the plasma proles of the compound were consistent when it was administrated as a type II formulation consisting of a MCT-ethoxylated glyceryl trioleate blend. The erratic and inconsistent absorption of the compound from the hydrophilic PEG formulation was attributed to its erratic and inconsistent precipitation in the GIT aqueous environment. Whereas, the improvement in the plasma proles from the type II formulation was attributed to the dispersion of the triglyceride into ne emulsion droplets (diameter <3 mm) with the compound still dissolved within.
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whereas the stimulation of lymphatic transport aids in the improved absorption and reduced hepatic metabolism of these compounds. Even relatively small quantities of LCT (e.g., 2 g) are thought to be capable of stimulating the gall bladder contraction and thereby elevating intestinal bile salts, phospholipids, and cholesterol levels. The extent of this stimulatory response appears to increase as the quantity of LCT administered increases.110 This effect is a likely contributor to the ability of LCT based formulations to reduce food effects and to enhance the oral bioavailability of some poorly soluble compounds. In contrast, administration of similar quantities of MCT was shown to have relatively limited effects on the gallbladder contraction and would not stimulate appreciable increase in the intestinal concentration of biliary-derived lipids.110 In addition, fatty acids with carbon chain length less than 12 directly enter the portal blood leading to the liver and then into the systemic circulation, thus circumventing the lymphatic transport mechanism. Thus, fatty acids with medium chain length are transported primarily by the portal blood, whereas ones with longer chain length are incorporated primarily into the chylomicrons and transported in the lymph.114 An understanding of how lipids of varying chain lengths of fatty acids could inuence the mode of transportation and absorption of dissolved compounds across the GIT provides valuable guidance to the formulation scientist in the selection of an appropriate lipid in the softgel ll formulation. The absorption of lipophilic compounds in fasted state was shown to be signicantly higher from a formulation containing even a small amount of LCT than that from a formulation containing either lipids of MCT or no lipids.121126 For example, Fischler et al.122 demonstrated a higher relative oral bioavailability and more rapid absorption of clomethiazole in fasting healthy volunteers when it was administered as a softgel containing arachis oil based formulation compared to a tablet formulation. The oral bioavailability of clomethiazole was also shown to increase with increase of coadministered oil amount. In another example, the bioavailability of the poorly soluble anti-malarial compound, halofantrine (aqueous solubility <0.1 mg/mL; LCT solubility >50 mg/ mL; log P 8.5) solubilized in LCT and administered in fasted state was shown to be similar to that from of a lipid-free formulation administered in-fed state.125,127 In lymph cannulated, fasted rats, the calculated relative systemic exposure of orally administered halofantrine (i.e., sum of plasma availability and lymphatic transport) was shown to increase with an increase in the fatty acid chain length of the coadministered lipid (C18-LCT, 22.7% of dose > C810-MCT, 19.2% > C4-SCT, 15.2% > C0-triglyceride free, 6.4%).121 This was attributed to the
relatively increased contribution of the intestinal lymphatic transport (C18, 15.8% of dose > C810, 5.5% > C4, 2.22% > C0, 0.34%) to the overall absorption of the compound. In a concurrent study, after oral administration of the three types of triglycerides (LCT, MCT, and SCT) to the lymph cannulated, fasted rats, the amount of LCT present in the lymph was three- and ninefold, respectively, higher after LCT administration compared to that after MCT and SCT administration. This was thought to be due to the stimulatory effect of exogenously administered LCT on the secretion and lymphatic transport of endogenous LCT, and the effect was hypothesized to diminish with a decrease in the chain length of the exogenously administered triglyceride (i.e., LCT > MCT > SCT).121,128,129 The lipophilic compounds administered in LCT were suggested to be transported in the lymph in association with the resynthesized exogenously provided LCT present in the core of the lymph lipoproteins (i.e., chylomicrons), as opposed to in association with the more polar, endogenously derived surface components such as phospholipid and protein.121 Though, these and many other studies demonstrated that LCT vehicles could enhance lymphatic uptake and yield relatively high concentrations of a lipophilic compound in the lymph, it should not be overlooked that the overall compound uptake may be some 50150 times greater than that observed to occur via the lymphatics due to the limited lymph ow.117,118 The relative oral bioavailability of another poorly soluble compound, danazol (aqueous solubility 0.42 mg/mL at 378C; LCT-soybean oil solubility 4.8 mg/mL at 378C; log P 4.5; BCS Class II130), in fasted beagle dogs from various formulations was also shown to be in the order of LCT solution LCTSMEDDS > MCT-SMEDDS > micronized powder.126 In a concurrent in vitro digestion studies, danazol was observed to precipitate more extensively upon aqueous dilution of the MCT-SMEDDS formulation compared to the LCT-SMEDDS formulation. The bioavailability of danazol from the micronized powder was signicantly higher in the fed state compared to that in the fasted state. Importantly, the relative bioavailability of danazol from the LCT solution and LCT-SMEDDS in the fasted state was shown to be statistically indistinguishable from that of the micronized powder administered in the fed state. These studies clearly demonstrate that an appropriate lipid formulation may be capable of achieving the same positive food effect as the postprandial administration of a poorly soluble compound. Another extensively studied example of lipidic formulation is of cyclosporin A (aqueous solubility 40 mg/mL; log P 2.92; BCS Class IV), which is supplied as a self-emulsifying oil solution (SEDDS) under the trade name Sandimmune1 (Novartis PharmaDOI 10.1002/jps
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ceuticals) and as a microemulsion preconcentrate (SMEDDS) under the trade name Neoral1 (Novartis Pharmaceuticals). Sandimmune1 cyclosporine ll formulation comprises of corn oil (LCT), linoleoyl macrogolglycerides (Labral1 M-2125-CS), and ethyl alcohol (Tab. 2), which forms a coarse emulsion on dispersion into an aqueous media.131 The triglyceride excipients in Sandimmune1 formulation require further lipolysis in vivo into diglycerides, monoglycerides, and free fatty acids, for efcient release and absorption of cyclosporine.52,132,133 In contrast, Neoral1 cyclosporine ll formulation comprises of corn oil mono- and di-glycerides, polyoxyl 40 hydrogenated castor oil (Cremophor1 RH 40), propylene glycol, ethyl alcohol, and dl-a-tocopherol (Tab. 2), which spontaneously forms a microemulsion with a droplet size below 100 nm when introduced into an aqueous media.131 The improved dispersion characteristics and presence of the rapidly absorbable monoand di-glycerides, which would not require further lipolysis in vivo (thus circumventing the lypolytic process) have been suggested to be responsible for the increased bioavailability and reduced inter- and intra-subject variability of cyclosporine from Neoral1 formulation.134,135 The bioavailability of cyclosporine from Neoral1formulation, for example, was shown to be signicantly higher (174239%), dose proportional, and free from food effects with reduced interand intra-subject variability compared to that from Sandimmune1formulation.134,135 In addition, the potential inhibitory effect of the polyethoxylated surfactant (i.e., Cremophor RH 40) in Neoral1 formulation on CYP3A and P-gp efux functionalities18,2022,136 may also contribute to the increase in bioavailability of cyclosporine from Neoral1 formulation.105 It is important to bear in mind that the inuence of the type of formulation and the type of lipid used in the formulation on the bioavailability can vary from one compound to other and with the amount of dose administered. Grove et al.,137,138 for example, demonstrated that the bioavailability of poorly soluble seocalcitol in rats was similar from a simple oil solution or a SMEDDS and was not inuenced by the chain length of the lipid used in the formulations. The bioavailability of another poorly soluble investigational compound, LAB687 (aqueous solubility 0.17 mg/mL; log P 4.7), was shown to be similar from a lipid formulation (corn oil glycerides, Cremophor RH 40, ethyl alcohol, and propylene glycol) and a PEG 3350-polysorbate 80 formulation in fasted beagle dogs.8 Fill Formulation Development Typically, solubility determinations are carried out by equilibrating a suspension containing an excess amount of a compound in a solvent at a constant
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temperature (e.g., 258C, 378C) and analyzing the supernatant, collected after centrifugation and ltration of the suspension, using an appropriate analytical method.104,117,130 The method is modied when developing a solution ll formulation for softgel encapsulation to take the water migration processes occur in a softgel into account.139 The solubility of a compound in a solvent is determined by dissolving increasing amounts of the compound in a xed amount of the solvent. A portion of the solution at each concentration is mixed with water to mimic water migration and retention processes occur in a softgel. The highest concentration of the compound at which no precipitation is observed in the presence of water at the equilibrium level is assumed to be the equilibrium solubility of the compound in the softgel compatible vehicle. When evaluating the solubility of a compound in a semisolid or a solid vehicle at room temperature, solutions of varying concentrations of the compound are prepared at a temperature above the melting point of the vehicle. The solutions are then allowed to solidify at room temperature. The solid solutions are observed periodically under a polarized microscope for the presence of any crystals of the compound.69 A hypothetical example of a softgel solution ll formulation development for a compound is illustrated in Table 3. In this example, the solubility of the compound in a neat vehicle is evaluated at increments of 10 mg/g (e.g., maximum solubility $50 mg/g). Depending on the type of vehicle (i.e., PEG, mixed medium chain glycerides, MCT, or LCT), the solutions are mixed with water at two levels that the ll solutions are expected to be exposed to during the encapsulation, drying phase, and subsequent equilibrium (Fig. 2). These solutions are placed at room temperature (RT) and accelerated physical stability conditions (e.g., 48C and 208C) for about a month. Solutions that do not show any crystallization, when observed visually and under a microscope, at a water level (higher) representing the primary drying phase within 24 h and at a water level (lower) representing the equilibrium phase for a month at all stability conditions are considered for further development (e.g., $20 mg/g in the example). It is, however, worth mentioning two aspects of water migration and its inuence on physical stability of a dissolved compound in softgels. First, though a compound dissolved in a vehicle for encapsulation may exhibit precipitation upon exposure to a higher water level during the primary drying phase, the compound may re-dissolve in the vehicle upon removal of the excess water during the secondary drying phase. Thus, it may be meaningful to ll the solution formulation into empty soft gelatin capsules (referred to as air-lls) and monitor the precipitationre-dissolution phenomenon during cycling of the
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Table 3. Experimental Design for the Development of a Hypothetical Softgel Solution Fill Formulation
Water Content Before Encapsulation (%)
a, 317
Mimicking Primary Drying
Mimicking Equilibrium
Fill Vehicle
Amount of Water to be Added (%) $16 $6 $0.1a, 253 $8 $4 $0.1a, 253 48C RT 208C 48C RT
PEG based $12 Mixed MC glycerides $0.15a, 318 MCT/LCT $0.1a, 253,319 Stability conditions Compound 208C Conc. (mg/g) Physical stability initial 10 H 20 H 30 H 40 H 50 H 60 Insoluble Physical stability 24 h 10 H 20 H 30 H 40 H 50 H 60 Insoluble Physical stability 1 month 10 H
48C
RT
208C
H H H H H
H H H H H
H H H H Xb
H H H H Xb
H H H H Xb
H H H H H
H H H H H
H H H H H
H H H H H
H H H H H
H H H Xb Xb
H H H Xb Xb
H H H Xb Xb
H H H H H
H H H H H
H H H H H
Observations are discontinued after 24 h as the ll formulation is expected to be exposed to this high level of water only during the rst 24 h
20 30 40 50 60
H H H H Insoluble
H H H H
H H H H
H Xb Xb Xb
H Xb Xb Xb
H Xb Xb Xb
(X) Precipitation (crashing out) of the compound; (H) no precipitation, but rejected due to precipitation of the compound within 24 h at a water level approximated during the primary drying process; (H) physically stable ll formulation for further chemical stability evaluation and subsequent encapsulation. a Typical water content initially present in the vehicle; no water addition is required. b May not be applicable to MCT/LCT based ll formulations as water is unlikely to migrate into these hydrophobic vehicles.
capsules between high humidity and low humidity conditions. A similar cycling procedure has been used by Raikes et al.,140 though, to study the moisture uptake by softgels under various relative humidity conditions. Secondly, the migration of water from the shell into the ll may be of an advantage when encapsulating lls formulated using the enhanced solubility system (ESS) techniques (discussed in Solubility Enhancers for Hydrophilic Vehicles Section), where a portion of the compound is present in its water soluble salt form. The chemical stability of the selected ll formulations is evaluated at 408C or higher in the presence of added water and gel swatches that represent various potential gelatin shell formulations used for encapsulation. Alternately, the selected ll formulations, with no added water, may also be lled into air-lls and exposed to elevated temperatures and relative humidities for
chemical stability evaluation. It is important to keep in mind that the selected gel swatches and air-lls for stability evaluation have compositions commonly used at various softgel manufacturers, as it would offer the exibility of manufacturing the nal softgel product at more than a single manufacturer. When a compound is soluble and has demonstrated stability in a softgel compatible vehicle, it can be encapsulated into softgels as a solution with minimal formulation effort. On the other hand, compounds that do not have sufcient solubility in softgel compatible vehicles may require encapsulation as suspensions. The dispersed material in a suspension should have a particle size of 180 mm or ner (pass through a #80 mesh) to achieve an acceptable blend uniformity during encapsulation and content uniformity in the nal softgel product.33 When a vehicle for a suspension ll formulation has any solubility for
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the compound, the dispersed material may undergo Oswald ripening and/or secondary nucleation,12 resulting in changes in the particle size distributions and/or in the polymorphic nature during the shelf-life of a softgel product. This aspect of stability a suspension ll formulation is typically investigated by subjecting the formulation with the added water (shown in Tab. 3) to the stress testing of cycling between 40 and 48C, in addition to other tests described above for a solution ll formulation. The samples are observed at the end of each cycle (e.g., 48 h at 408C, followed by another 48 h at 48C may be considered as one cycle) for any changes in the particle size, morphology, and polymorphism. Temperature cycling may accelerate the dissolution of the suspended compound in the formulation vehicle at the higher temperature and re-crystallization upon cooling, thus provide valuable information on the physical stability of a softgel product during its shelflife. However, the transformation may occur rapidly or slowly and may be reversible (enantiotropic) or irreversible (monotropic).12 A suspension ll formulation may also require a suspending (thickening/viscosifying) agent to prevent settling of the dispersed material and to maintain homogeneity throughout the encapsulation process.33 The widely used suspending agents for oil based formulations include beeswax,141 hydrogenated vegetable oils,142 and glycerol esters of fatty acids with low HLB values (e.g., Gelucire1 33/01, Gelucire1 39/01, Gelucire1 43/01, Compritol1 888, from Gattefossee Corporation).143,144 These suspending agents, due to their hydrophobic and high viscous nature, could also minimize the migration of water from the shell into the ll and the diffusion of water soluble compounds from the ll into the shell and thereby improve the physical stability of a softgel product. The suspending agents used for polyethylene glycol based formulations include higher molecular weight polyethylene glycols (e.g., PEG 1500, PEG 4000, PEG 6000),66 cellulose polymers,73,74 colloidal silicon dioxide, polyvinylpyrrolidone, calcium acetate,75 and mixtures of mono-, di-, and triglycerides/mono- and di-fatty acid esters of polyethylene glycols (e.g., Gelucire1 44/14, Gelucire1 50/13, from Gattefossee Corporation). Polymorphism is a common phenomenon among many pharmaceutical active ingredients and excipients.145147 Substantial differences can exist in the rate of dissolution and bioavailability of the various polymorphic forms of a compound.146,148151 These effects of polymorphism are more critical especially in the case of compounds belonging to BCS class II and class IV. It is critical to start the ll formulation development with a stable polymorph to prevent any potential precipitation of the dissolved compound due to conversion of an unstable or a metastable form into the stable form. Ritonavir softgel product (Norvir1,
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Abbott Laboratories) is a classic example of how polymorphic transformation of a soluble polymorph (I) to a less soluble form (II) could affect the quality of a softgel product.152,153
SHELL FORMULATIONS
A softgel shell formulation typically consists of a lmforming material, such as gelatin, water dispersible or soluble plasticizer(s), and water. The formulation may also contain other minor additives, such as opaciers, colorants, avors, sweeteners, and preservatives. Softgels may also be coated with a variety of polymers for certain targeted enteral delivery applications.154 Gelatin The Unites States Pharmacopeia/National Formulary (USP/NF) denes gelatin as a product obtained by the partial hydrolysis of collagen derived from the skin, white connective tissue, and bones of animals. Gelatin can be derived from many different sources of collagen with cattle bones, hides, pigskins, and sh being the principle commercial sources. It contains a mixture of water soluble proteins (8490%), mineral salts (12%), and water (815%). The protein fraction contains almost entirely of amino acids linked by amide bonds forming a linear polymer with a molecular weight ranging from 15000 to 250000 Da.155158 The water content in gelatin usually originates from its manufacturing process.34,159 Gelatin is derived from collagen by thermal denaturing with the aid of either a dilute acid (type A gelatin) or a dilute alkali (type B gelatin). Gelatin is usually characterized by the mode of its production and how it is produced has marked inuence on its properties. Gelatin is amphoteric in nature with its isoelectric points (IEP) ranging from 7.0 to 9.0 for type A gelatin and from 4.7 to 5.3 for type B gelatin, respectively.158 The alkaline hydrolysis causes a greater degree of deamidation of the asparagine and glutamine amino acids in collagen, resulting in the production of a larger number of free carboxylic acid groups in gelatin than that from acid hydrolysis. The greater degree of deamidation and the resulting larger number of free carboxylic acid groups from the alkaline hydrolytic process accounts for the relatively lower isoelectric point of type B gelatin compared to that of type A gelatin.160 Type A gelatin usually displays relatively higher plasticity and elasticity than type B gelatin, whereas type B gelatin displays relatively higher gel strength. Commercially available gelatin is odorless, tasteless, and free-owing granular material with a lightamber to light-yellowish tint.158 The most favorable aspect of gelatin for its use in softgels is its ability to
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form thermoreversible gel in water, that is, ability to dissolve in hot water and form a gel upon cooling, a must have quality for sealing the softgels during encapsulation. Gelatin is soluble in glycerin, propylene glycol, dilute acids, and dilute alkalis, but precipitates in strong acids and alkalis. The rate of dissolution of type B gelatin is usually higher than that of type A gelatin at a given pH of the aqueous medium.161 The dissolution of gelatin, irrespective of its type, was shown to be not inuenced signicantly by pH at pH values above 3, but was shown to increase and reach a plateau at pH values below 3. The higher dissolution of gelatin at lower pH may be attributed to the protonation of amino groups present in the gelatin. However, the dissolution of gelatin at lower pH was shown to decrease in the presence of added salts, such as sodium chloride and potassium chloride.161 Gelatin is insoluble in most organic solvents, such as alcohols, acetone, and chloroform.156 It is important to keep these solubility characteristics of gelatin in mind during the development of dissolution methods for softgel products. Gelatin undergoes hydrolytic degradation (depolymerization) in the aqueous gels, the rate and extent of which depend on the pH, temperature, and time, the reaction is allowed to proceed.34,94,162,163 The depolymerization reactions in gelatin may be further accelerated by the lowering of its molecular weight.34 The hydrolytic degradation of gelatin results in the reduction of the viscosity and gel-forming ability of a gelatin solution, and in the formation of weak seams during softgel encapsulation. Though gel strength and viscosity are the two parameters commonly used to measure the extent of gelatin hydrolytic degradation, the gel strength has been known to be more sensitive indicator of the degradation reaction.94,162 The degradation of gelatin (expressed as loss of gel strength as a function of time) was shown to follow rst order reaction kinetics, with the reaction rates varying according to the pH and temperature. In addition, the rate constants were shown to be minimum between pH values 4 and 7, with the rate accelerating on either side of this pH region, as shown in Figure 5.94 The minimum hydrolytic degradation of gelatin within the pH range of 47 was further corroborated by the data obtained from Courts investigations,163 where minimum loss of average molecular weight of gelatin was observed within this pH range. The pH of a gelatin solution remains constant when the degradation reaction takes place at the isoelectric pH of gelatin.163 In contrast, the pH of the solution shifts slightly towards the isoelectric pH when the pH of the reaction medium is other than its isoelectric pH and the shift becomes larger at high pH values.162,163 Acid treated gelatins (type A) are more susceptible to alkaline degradation than to acid degradation, whereas alkaline treated
Figure 5. Inuence of pH and Temperature on the First Order

Rate Constant (h1) for Decay of Gel Strength of Limed Ossein Gelatin with Bloom Strength 250 g and Isoelectric pH 4.75 (Data adopted from Croome94).
gelatins (type B) are more susceptible to acid degradation.162 From the studies on the hydrolytic degradation of gelatin, Courts163 suggested that the peptide bonds involving the amino groups of serine and threonine were labile to both acidic and basic hydrolysis, whereas aspartic acid peptides were susceptible to acid hydrolysis only. The glutamic acid peptide bonds were reported to be stable, while glycine peptide bonds were of intermediate in stability. Gelatin is considered as an inactive ingredient by the Food and Drug Administration (FDA). Softgel manufacturers quality control testing for gelatin, among other things, includes bloom strength, viscosity, iron content, and microbial testing.33,50 Bloom strength, also known as jelly strength, is expressed as the weight in grams that, when applied with a 12.7 mm diameter plastic plunger, will produce a depression exactly 4 mm deep in a jelly containing 6.67% w/w of gelatin in water matured for 1618 h at 108C. Bloom strength of gelatin used in a softgel shell may vary from 150 to 250 g, with the higher the bloom strength, the more physically stable is the resulting softgel shell. As the cost of a softgel product is related directly to the bloom strength of gelatin used, gelatin of a higher bloom strength is usually reserved only when necessary to improve the physical stability of a softgel product or for large size softgels which require greater structural strength during manufacture.33 Viscosity determination is performed on a 6.67% w/w concentration of gelatin in water at 608C and usually ranges between 25 and 45 millipoise. Iron levels present in the gelatin raw material is derived mainly from the water used in its production and should not
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exceed 15 ppm as higher levels may potentially result in the color reactions with other softgel components. Gelatin is an excellent growth medium for many bacteria and thus requires considerable care during its manufacture and handling to avoid contamination. Plasticizers The high glass transition temperature of anhydrous gelatin (Tg > 1008C)45,164169 prevents it from forming a exible and acceptable lm readily during the manufacturing of gelatin capsules. Water is an effective plasticizer for gelatin and reduces the Tg of gelatin proportionally to its water content.45,165,167,169,170 Coppola et al.,169 for example, reported a decrease in the Tg of gelatin from 1608C to 208C when the water content in gelatin was increased from 2 to 28% w/w. However, due to its volatile nature, water will be lost during the drying process resulting in a brittle and fragile shell. Thus, nonvolatile plasticizers are included in the production of gelatin ribbons for softgels. The nonvolatile plasticizers are hypothesized to substitute for water in the vicinity of the protein chains and reduce the proteinprotein interactions with a consequent increase in the mobility of protein chains and a decrease in the Tg of gelatin.169,171173 In addition, a plasticizer, due to its hygroscopic nature, may promote absorption of moisture by gelatin that also contributes to the reduction of the forces between the adjacent polymer chains.155,174 Vanin et al.,174 in effect, considered the reduction in the Tg of the gelatin lms as a consequence of the total number of moles of all plasticizers (i.e., nonaqueous plasticizers and water) present in the lms. Thus, the extent to which a plasticizer could impart exibility to a gelatin lm is determined by its hygroscopicity and its ability to interact with protein chains and reduce the protein protein interactions within gelatin.155,174,175 The reduction in the proteinprotein interactions results in improved exibility and handling of the shell material during its manufacturing and shelf-life. Typical plasticizers used in the softgel shell formulations include glycerin, sorbitol, partially dehydrated sorbitol (a blend of D-sorbitol, 1,4-sorbitan, mannitol, and water; e.g., Sorbitol Special1, from SPI Pharma; Anidrisorb1 or Polysorb1, from Roquette), maltitol (hydrogenated corn syrup; e.g., Lycasin1, Roquette), mannitol, propylene glycol, low molecular weight polyethylene glycols, or a blend thereof. Selection of a plasticizer type and its concentration (expressed as the plasticizer-to-gelatin ratio, P/G) in a shell formulation is determined by gelatin type, composition of ll formulation,60,161 and compatibility with the ingredients present in a ll formulation.98,100 Plasticizers are used typically at about 1530% w/w of the total wet mass of a shell
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formulation at the time of encapsulation.39,4042,176 The addition of increasing amounts of a plasticizer alters the physical properties of a gelatin lm resulting in an increase in its exibility, elongation at break, water retention, water vapor permeability, oxygen permeability, and volatile solute permeability, and a decrease in its Tg, tensile strength, and elastic modulus.43,56,57,60,155,174,175,177 Among the various plasticizers studied, glycerin was reported to be the most effective and practical plasticizer, irrespective of type of gelatin used in a shell formulation.171,175 The higher plasticizing efcacy of glycerin was attributed to its lower molecular weight178 and higher hygroscopicity175 than other higher polyols. When compared among various nonvolatile plasticizers, the number of moles of a plasticizer in a given amount would be higher in glycerin, and thus their effect on reducing the number of interactions between the protein polymeric chains would be more intense.175,179 It also has been theorized that a plasticizer with a lower glass transition temperature (Tg) would have a more pronounced plasticizing effect. In this way, the effectiveness of glycerin might also be explained by its lower Tg (938C) as compared to sorbitol (38C).175,180 Propylene glycol is more effective as a gelatin plasticizer compared to glycerin.171 However, due to its higher solvent power for gelatin, propylene glycol affects the formation of the gel structure adversely, that is, it acts as more of a gel structure beaker. In addition, due to its higher volatility compared with glycerin, the use of propylene glycol results in the considerable deterioration in the mechanical strength of the shell material with time.171 Furthermore, gelatin sheaths containing propylene glycol as the plasticizer are substantially tackier than those containing glycerin or sorbitol as the plasticizer and require much lower cooling drum temperatures to extract the sheaths from the drums during softgel manufacture.37 The ability of a polyethylene glycol (PEG) to act as a plasticizer is determined by its hydrogen bonding potential with the protein chains in gelatin that in turn is inuenced by factors, such as the number of hydroxyl groups per mole, molecular size, solubility, and polarity of the PEG. PEG of a lower molecular weight has a larger number of hydroxyl groups per mole and a higher hygroscopicity compared to those of a higher molecular weight PEG and thus exhibits a more pronounced plasticizing effect than that by the latter. Gelatin lms plasticized with polyethylene glycols have also shown to exhibit a tendency for the plasticizer to migrate to the surface of the lms, a phenomenon referred to as blooming or blushing.57 This phenomenon is thought to take place when the plasticizer concentration exceeds its compatibility limit in the polymer, thus causing phase separation
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and physical exclusion of the plasticizer from the polymer.181 Glycerin, due to its extreme hygroscopic nature, can inuence gelatin to pick up substantial amount of moisture quickly,169 leading to a soft, tacky, and bloated softgel sheath that will ultimately break down or result in softgels sticking together with time. Sorbitol, on the other hand, may prone to crystallization from the lms that are stored at low to intermediate relative humidity conditions due to the insufcient availability of water to keep the plasticizer in solution (i.e., blooming or blushing).179,182 The crystallization of sorbitol would decrease the amount of plasticizing sorbitol that in turn is expected to increase the molecular interactions within the gelatin network and to change the mechanical properties of the lms.179 Mannitol has also been reported to exhibit a similar tendency to crystallize from gelatin lms.57 It is sometimes advantageous to blend sorbitol with glycerin that would yield a better control of the overall moisture content of the softgel sheath. Partially dehydrated sorbitol (a blend of D-sorbitol, 1,4-sorbitan, mannitol, and water), in comparison, tends to pick up less moisture than glycerin and also not to prone to crystallization as regular sorbitol. The effectiveness of partially dehydrated sorbitol as a plasticizer is attributed primarily to its 1,4-sorbtan content and the interactions of 1,4-sorbitan with the gelatin matrix.172 Gelatin lms produced with glycerin as a plasticizer are less resistant to moisture and more permeable to oxygen and volatile ingredients than those produced with a higher polyol plasticizer, such as xylitol, sorbitol, maltitol, or a blend of glycerin with a higher polyol.43,60,175,183 The oxygen permeability through a gelatin lm has been shown to increase exponentially with an increase in glycerin concentration in the lm and with an increase in relative
humidity to which the lm is subjected to.43 During concurrent studies, the moisture content of the lm has also been shown to increase with an increase in glycerin concentration in the lm and with an increase in relative humidity to which the lm is subjected to. Based on these observations, Hom et al.43 theorized that the plasticizers and environmental relative humidity conditions control the equilibrium water content of a gelatin lm, and this equilibrium water content has the greatest effect on the oxygen permeability through the lm. In a comparative study, the oxygen permeability coefcients of gelatin lms containing glycerin/sorbitol (1:1) blend, hexaglycerol, and decaglycerol were reported to be about 38.7%, 20.8%, and 19.5%, respectively, of that of a gelatin lm containing glycerin, at 43% plasticizer concentration, 72% relative humidity, and room temperature.43 Thus, the use of a nonglycerin plasticizer or a blend of glycerin and a higher polyol is recommended when encapsulating oxygen sensitive compounds in the softgels. Volatile ll components, such as ethyl alcohol, can readily diffuse through conventional softgel shells and usually disappear by the end of the drying processes during the softgel manufacture.60,183 Moreton and Armstrong60,183 have studied the inuence of plasticizer type and relative humidity conditions on the lm moisture content and diffusion of ethyl alcohol through the gelatin lms in details. A brief summary of the results reported by these researchers is presented in Table 4. The diffusion of ethyl alcohol through the gelatin lms plasticized with glycerin was shown to accelerate with an increase in the lm moisture content. A similar trend, though at a signicantly much lower rate, was also seen in gelatin lms plasticized with xylitol. It appears from Table 4 that the relative humidity conditions control the equilibrium water concentration in a gelatin lm,
Table 4. Inuence of Plasticizer Type and RH on Moisture Content and Diffusion of Ethyl Alcohol through Films Made from 150 Bloom Lime Bone Gelatin60,183
Plasticizer Type and Concentrationa Glycerin, 20% w/w Exposure to % RHb 11 33 54 75 33 33 54 75 75 Moisture Content % w/w Range 4.566.44 7.439.32 13.2019.80 30.7034.10 8.588.82 8.008.14 13.1014.39 26.5033.67 17.0023.10 Apparent Diffusion Coefcient mm2 min1 Range 3.453.81 105 4.605.24 105 8.6146.2 105 51.768.1 105 No diffusion detected No diffusion detected 0.7591.68 105 5.6722.1 105 1.161.47 105
Sorbitol, 20% w/w Xylitol, 20% w/w
Lycasin, 20% w/w

a b
Based on total wet mass. Exposed to the selected relative humidity (RH) at ambient temperature (21.523.78C).
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and this equilibrium water concentration appears to have the greatest effect on the diffusion of a volatile ll component through the lm, that is, for a given plasticizer type, the higher the moisture content of a gelatin lm, the more rapid the diffusion of a volatile component through it. However, the diffusion process was signicantly lower through the gelatin lms containing a higher polyol plasticizer, such as xylitol, sorbitol, or lycasin, compared to that through the lms containing glycerin as the plasticizer, at similar lm moisture contents. Thus, the loss of a volatile ll component due to diffusion can be minimized by the use of a higher polyol plasticizer, maintaining low shell moisture content, and protecting the softgel product against high humidity conditions. Colorants and Opaciers Coloring agents are included in a softgel shell formulation to provide elegance to a softgel product and also to provide a distinctive appearance that may serve to differentiate a particular softgel product from others that have a similar physical appearance. The coloring agents can be dyes (water-soluble substances), lakes (insoluble forms of a dye that result from its irreversible adsorption onto a hydrous metal oxide), inorganic pigments (substances such as titanium dioxide or iron oxides), or natural colorants (colored compounds not considered dyes per se, such as riboavin).184 The most important properties of a coloring agent are its depth of color and resistance to fading over time. Coloring agents can be graded on their efciency in reecting desired colors of visible light as well as on their molar absorptivities at characteristic wavelengths of absorbance.184 Coloring agents are subject to federal regulations and consequently the current regulatory status of a given substance must be determined before it is used. It is desirable that the coloring agents should be physically and chemically nonreactive with other ingredients present in the softgel product. Anionic dyes are known to interact to a greater extent with a cationic type A gelatin than with an anionic type B gelatin.185 These interactions could potentially effect the disintegration of the gelatin shell. An opacier is included in a shell formulation to provide light resistance when photosensitive compounds are encapsulated into softgels. An opacier may also be included in a shell formulation when encapsulating an unaesthetic ll formulation, such as a disperse system that is prone to phase separation or sedimentation. Titanium dioxide is the most commonly used opacier and is typically used at about 0.51.0% w/w of a shell formulation to impart sufcient opacity to the shell. Titanium dioxide is a white, odorless, tasteless, inert, nonhygroscopic powder186 that has been shown to undergo no
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observable interactions with gelatin and other ingredients used in the softgels.187 Due to its high refractive index (2.552.76), titanium dioxide has excellent light-scattering properties and the extent of light-scattering by titanium dioxide can be altered by varying its particle size186,188,189 and concentration used in a shell formulation.190 As Rayleighs theory implies, the shorter wavelengths of light are more efciently scattered by smaller particles, that is, the ner the particle size of the opacier the more effective it is in scattering the UV light below 400 nm. However, as the particle size of the opacier reaches below 50 nm, its scattering power decreases in the visible range making the lm more transparent than one with a larger particle size.188,189 Titanium dioxide is highly hydrophobic and generally occurs as aggregated particles that should be dispersed and wetted thoroughly before its addition to the molten gel mass.191 The effectiveness of a shell material to provide light protection to an encapsulated compound is critically dependent on how well the opacier is dispersed in the gel mass. Ideally, for an opacier to be more effective against UV light transmittance, it should be dispersed as individual crystals or small agglomerates of two or three crystals. Aggregates of many ner crystals behave as though they are one large particle, thus scattering visible light and exhibiting poor effectiveness in the UV range.188 The light transmission through a gelatin lm can also be reduced substantially either with the increase of its thickness at a given opacier concentration or with the increase of the opacier concentration in the lm.190 The light transmission through a gelatin lm was shown to be diminished with the increase of titanium dioxide concentration up to 1% in the lm and plateauing afterwards.190 The addition of an opacier to a shell formulation may also potentially increase the tortuosity of the path that the permeating oxygen and light must ow through to reach the ll.43 However, the effect of an opacier on the permeability of oxygen through gelatin lms was shown to be observable only at opacier concentrations substantially higher than what is commonly used in a capsule shell formulation.
DISSOLUTION
Dissolution of Softgel Shell The availability of a compound formulated in a softgel for absorption depends on the initial dissolution and rupture of the softgel shell and subsequent release and dissolution of its ll contents in the GIT uids. Thus, these two processes need to be monitored during the release and shelf-life of a softgel product.
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Problems in the dissolution and rupture of the softgel shell may become apparent upon aging, when exposed to physical conditions, such as heat,192,193 high temperature and humidity, UV radiation, g-radiation,194 and rapid drying,47 and when exposed to chemical substances, such as aldehydes, ketones, imines, and carbodiimides.195,196202 These problems are attributed to cross-linking of gelatin (pellicle formation) that causes the gelatin shell to become swollen, tough, rubbery, and insoluble in water. Cross-linking of gelatin gives rise to the formation of a very thin lm during the dissolution testing of a softgel product. The lm is mechanically weak and can easily be punctured. However, the lm does not disrupt easily with gentle agitation under normal dissolution conditions.203 Mechanism of Gelatin Cross-Linking The ultimate effects of exposure to elevated temperatures on the physical properties of the gelatin shell are known to be similar to those of exposure to aldehydes, though the mechanisms of
chemical reactions occurring within the gelatin are distinctly different.204,205 Physically, exposure of gelatin shell to either elevated temperatures or aldehydes results in a decrease of its disintegration, dissolution, and swelling properties, and an increase of its gel strength, a clear indication of the formation of three dimensional networks within the gelatin. Chemically, aldehydes are known to form methylene bonds between two amino groups on adjacent gelatin chains or within the same chain, as illustrated in Figure 6. The aldehyde induced cross-linking of gelatin is thought to involve the eamino functional groups present in the lysine moieties and the guanidino functional groups present in the arginine moieties of the gelatin chain.196,197,206211 Both of these amino acids, lysine and arginine, have long, reactive side chains that can extend farther out from the polypeptide chain than other groups and thus can participate more easily in the inter and intra molecular reactions.207 In addition, hydrogen bonding is proposed to provide the added stability to the lysine-arginine cross-link
Figure 6. Possible mechanism of formation of methylols of lysine and arginine and subsequent
cross-links formation in gelatin (adopted from Taylor et al.,207 Albert et al.,209 Gold et al.210).
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and arginine-arginine cross-link (Fig. 6). Evidence obtained from 13C nuclear magnetic resonance (NMR) studies using 13C labeled formaldehyde as a cross-linking agent strongly suggests the formation of methylols (i.e., hydroxylmethyl) of lysine residues initially and of arginine residues later, which react together resulting in the formation of lysine-to-arginine and arginine-to-arginine crosslinks in gelatin, but no evidence has been found in the formation of lysine-to-lysine cross-links in gelatin exposed to aldehydes.207209 As the formation of arginine methylols was identied to coincide with the initiation of gelatin cross-linking reactions, its formation was hypothesized to be the rate limiting step in the cross-linking of gelatin. The rate of crosslinking in gelatin by aldehydes was shown to be strongly inuenced by humidity with maximum cross-linking occurring around 6070% humidity.209 Due to the high pKa value of the e-amino functional group (pKa $ 10.79) in lysine and of the guanidino functional group (pKa $ 12.48) in arginine, both these functional groups exist in their protonated forms at acidic pH and thus are not expected to be available to react with aldehydes.210 In contrast, since both of these functional groups exist primarily in their unprotonated forms at alkaline pH, they can potentially react with aldehydes, resulting in crosslinking. Gold et al.210 suggested that ll formulations, containing excipients suspected to be contaminated with aldehydes, should be formulated at the lowest possible pH to prevent gelatin crosslinking. In contrast to the cross-linking mechanism in the presence of chemical agents, elevated temperatures are known to promote condensation reactions between a carboxylic group on a gelatin chain and an amino group on an adjacent gelatin chain (or within the same chain), as illustrated in Eq. (1).192193 Eq. (1) shows the effect of elevated temperatures on gelatin Chain 1 COOH H2 N Chain 2 ! Chain 1 CO NH Chain 2 H2 O (1)
The aldehyde and other carbonyl impurities in softgels may originate from the autooxidation of materials containing polyoxyethylene moieties in their structures (e.g., polyethylene glycols, methoxypolyethylene glycols, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyl 40 hydrogenated castor oil).95,213218 Rayon coiler, included in the package presentations, is known to be another source that produces furfural (2-furaldehyde) at the accelerated stability conditions that could potentially cross-link gelatin.219,220 On the other hand, drug molecules containing carbonyl functional groups in their structures (e.g., nimesulide, rofecoxib, macrolide antibiotics) may also induce the cross-linking of gelatin and thereby reduce the dissolution of the shell material.221,222 Minimizing Gelatin Cross-Linking The cross-linking of gelatin in a softgel shell can be reduced by using excipients with low aldehyde content in the ll formulation, by using excipients containing abundant free amino groups (e.g., glycine, lysine) in the shell formulation that can compete with the amino groups present in the gelatin chain for the available aldehydes originating from the components used in the softgel (i.e., aldehyde scavengers), and/or by masking the amount of amino groups available along the molecular chain of the gelatin through covalent bonds with suitable masking agents.223 Succinic acid is an agent often used to mask the amino groups present in the gelatin chain through covalent bonds (succinization). The dicarboxylic acid nature enables succinic acid to both the reaction of one carboxylic group with an accessible amino group in the molecular chain of the gelatin while the second carboxylic group concurrently provides steric prevention of access of the cross-linking agent. However, a disadvantage of the succination approach is the gelatin shell prepared using the succinated gelatin is usually highly permeable to volatile solvents (e.g., ethyl alcohol) and migratable ingredients (e.g., propylene glycol). Incorporation of both an amino acid (e.g., glycine) and a carboxylic acid (e.g., citric acid) into the powderll of hydrochlorothiazide hard gelatin capsule was shown to provide a reduction in the cross-linking of gelatin.224,225 The carboxylic acid was believed to provide an acidic environment necessary to minimize the hydrolytic degradation of hydrochlorothiazide into its carbonyl impurity, whereas the amino acid was believed to function by acting as the carbonyl scavenger. However, this approach is fraught with the disadvantage of limited solubility of the stabilization excipients in the nonaqueous vehicles commonly used in softgels.226 To circumvent these solubility issues, the WIPO patent application WO 03/103582176
Whether it is aldehyde induced or heat induced, cross-linking of gelatin results in the formation of three dimensional molecular networks of a higher molecular weight with the loss of ionizable groups (i.e., R-NH2 and R-COOH) than the original molecules, leading to the reduced solubility of gelatin. Alternately, the loss of ionizable groups in gelatin and the resulting decrease in its solubility may also arise from the ionic, hydrogen, and van der Waals interactions of these groups with other compounds used concurrently in the shell formulation, such as FD&C red #3 and FD&C red #40 dyes.185,212
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proposes the use of an amino acid moiety (e.g., glycine, lysine) in the shell and a softgel compatible ester of carboxylic acid (e.g., tocopherol acetate, tocopherol succinate, D-alpha tocopheryl polyethylene glycol succinate-TPGS) in the shell, ll, and/or lubricant to reduce the cross-linking of gelatin. The extent of gelatin cross-linking in the softgel shell may also be inuenced by the type of functional group(s) present in the structures of the compounds encapsulated. Compounds containing either a primary amine group(s) (e.g., isoniazid, acyclovir) or a secondary amine group(s) (e.g., ethambutol) may interact with the aldehyde impurities present in the ll formulation, that is, act as aldehyde scavengers, and thereby prevent the cross-linking of gelatin.222 Dissolution Testing: Inuence of Digestive Enzymes on Gelatin Cross-Linking The USP Chapters <711> and <2040> on Dissolution227 provide guidance and procedures for dissolution testing for dosage forms administered orally. For gelatin capsules that failed tier 1 dissolution testing (i.e., in a medium with no enzymes) due to gelatin cross-linking, the USP recommends the use of digestive enzymes (i.e., pepsin or pancreatin) in the dissolution medium during tier two dissolution testing. These enzymes digest the cross-linked gelatin and thereby promote the dissolution and rupture of the cross-linked gelatin shell. The use of these digestive enzymes in the dissolution medium is justied on the grounds that such enzymes are also present in the GIT.228,229 Softgels that failed the tier 1 dissolution testing but passed the tier 2 dissolution testing (Fail/Pass) were shown to be bioequivalent to those which passed the tier 1 dissolution testing, whereas softgels that failed both tiers of dissolution testing (Fail/Fail) were shown to be bioinequivalent to those passed either one or both tiers of dissolution testing.230 Severe crosslinking of gelatin (Fail/Fail) was thought to result in the decreased availability of its peptide bonds towards the proteolytic enzymes (i.e., pepsin and pancreatin), leading to decreased rate and extent of proteolysis of gelatin by these enzymes. The proteolytic enzymes may also cease to recognize the carboxyl ends of the aldehyde-derivatized lysine and arginine.231 In some cases, though the severe crosslinking may not adversely affect the bioavailability (AUC(01) and Cmax) of a compound, but it could potentially delay the onset of its absorption (Tmax) due to the delayed shell rupture in vivo.231 Based on a detailed gamma scintigraphy study to identify the time and location of disintegration of cross-linked and noncross-linked capsules in vivo, Digenis et al.231 suggested that the aldehyde induced cross-links were more susceptible to cleavage by the pancreatic
enzymes in the small intestine as compared to the gastric enzymes like pepsin. It may be the cause for the delayed capsule rupture in vivo. Dissolution of Softgel Fill Changes in the dissolution of a ll material are usually apparent (a) when there is a change in particle size distributions (e.g., due to Oswald ripening) and/or polymorphic nature (e.g., due to secondary nucleation) of the suspended material in a suspension ll formulation,12 (b) when there is crystallization of a solubilized compound from a solution ll formulation,153 or (c) when a poorly soluble compound is dissolved in hydrophilic solvents and cosolvents (e.g., type IV formulations under Poutons LFCS109). In the latter case, upon dilution with the GIT uids in vivo or with the dissolution medium in vitro, the hydrophilic ll vehicle may dissolve or disperse in the aqueous uids and thereby expose the solubilized water-insoluble compound to aqueous uids, leading to erratic and inconsistent precipitating of the compound (crashing out).70 Surfactants are commonly used in the dissolution medium during the dissolution testing of poorly soluble compounds and oily formulations.1,144,229,232236 The use of surfactants in the dissolution medium for the dissolution testing of poorly soluble compounds has been proposed to be physiologically meaningful as these surfactants mimic those natural surfactants, such as bile acids, bile salts, and lecithin present in the GIT.232,233 Additionally, Buri and Hainbert-Droz237 suggested that the natural surfactants could be interchanged with a synthetic surfactant, such as sodium lauryl sulfate, for solubilizing poorly soluble compounds. The selection of a type and concentration of a surfactant and other solutes used in the medium for dissolution testing is based on a variety of factors, such as (a) aqueous solubility, ionic nature (pKa; pHsolubility prole), and dose of the compound; (b) compatibility of the surfactant with the compound; (c) compatibility of the surfactant with the gelatin shell;238241 (d) critical micellar concentration (CMC) of the surfactant; and (e) degree of partitioning of the compound into the surfactant micelles (i.e., micellar loading).234 Some commonly used surfactants in the dissolution medium include sodium lauryl sulfate (SLS), polyoxyethylene sorbitan monolaurate (Polysorbate 20), cetyltrimethylammonium bromide (CTAB), polyoxyl castor oil (Cremophor EL), hexadecyltrimethylammonium bromide (HTAB), polyethylene glycol tert-octylphenyl ether (Triton), nonylphenol ethoxylate (Tergitol), cyclodextrins, and lecithin.234 Use of aqueousorganic solvent mixtures is strongly discouraged as the dissolution medium for softgels as these solvents
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could potentially prevent dissolution of gelatin shell even when it is free from cross-linking, resulting in reaching misleading conclusions. In addition, the use of these aqueous-organic medium has no relevance to the physiological environment and is not likely to generate meaningful data for in vivo interpretation.229,232,233 Surfactants, used to improve the dissolution of poorly soluble compounds and oily formulations, are also known for their denaturing effects on the digestive enzymes used in the dissolution medium for cross-linked softgel formulations.242,243 The USP recommended levels of pepsin or pancreatin may be sufcient for the digestion of cross-linked softgels in the absence of a surfactant. The cross-linked softgels were shown to pass the tier two dissolution testing only when the enzyme was introduced into the medium initially followed by the surfactant few minutes afterward. These softgels failed to meet the dissolution specication when enzyme and surfactant were introduced into the medium together at the onset of dissolution testing. Thus, it was recommended to introduce the surfactant into the dissolution medium after the initial enzyme digestion of cross-linked softgels had occurred.244,245 Sodium lauryl sulfate, an anionic surfactant, could bind to the cationic charges on gelatin at pH values equivalent to gastric pH.239,241,246248 Due to the high pKa values of the amino functional groups in gelatin, these groups exist in their protonated form at gastric pH and thus are expected to undergo ionic interactions with the negative charges on the anionic surfactant. The anionic charges of gelatin, on the other hand, may bind to cationic surfactants, such as cetylpyridinium chloride, dodecylammonium chloride,249 and dodecyl amine hydrochloride.246 These interactions may inuence the solubility and dissolution of the capsule shell.241,247 The rate of dissolution of a gelatin shell in acidic solutions (pH < 5), for example, was shown to decrease as the concentration of sodium lauryl sulfate in the dissolution medium was increased.241 In addition, the rate of dissolution slowdown caused by the surfactant was shown to be more pronounced with the increased ionic strength in the medium. Use of a nonionic surfactant (e.g., polysorbate 20, polysorbate 80) may be considered in place of an ionic surfactant during the dissolution testing of poorly soluble compounds to minimize the gelatin-surfactant interactions and ensuing slowdown of disintegration of gelatin shells.247 Equally important, the impurities present in a surfactant and other electrolytes used in the dissolution medium could inuence the CMC of the surfactant, and size and loading capacity of micelles for a compound and thus inuence the ultimate solubility and dissolution rate of the compound in the dissolution medium.234,241,250,251 Therefore, the type
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and concentrations of solutes in the dissolution medium used either to adjust pH, buffer strength, or ionic strength of the dissolution medium, or to enhance the solubility of a poorly soluble compound, could play a critical role in the dissolution of a softgel product. It is worthwhile to evaluate all these variables during the development of dissolution methodology for a softgel product. Examples of dissolution procedures used for some marketed softgel products are presented in Table 2.
STABILITY
Physical Stability Crystallization of Solubilized Compounds Due to the high initial water content of the shell formulation at the time of encapsulation (! 30%),39,40,41 water migrates from the shell into the ll and vice versa during the drying and subsequent equilibrium processes (Fig. 2). The rate and extent of water migration is inuenced by the composition of shell formulation (e.g., type and concentration of plasticizer, presence of additives),37,43 composition of ll formulation,40,41,69,72,139 and environmental conditions to which the softgels are subjected to.43 The improved bioavailability of a compound encapsulated in a solubilized form is due to the presentation of the compound at the site of absorption as a solution. The objective of improving bioavailability of a compound through solubilization may be defeated if the solubilized compound crystallizes either within the softgel due to water migration68,69 or upon coming into contact with the aqueous uids in the GIT.70,72 Studies by Serajuddin et al.69 demonstrated gross crystallization of a poorly soluble test compound in the softgels when the compound was encapsulated as a PEG 400 based solution. However, no such crystallization of the compound was observed in the softgels when the test compound was encapsulated as a Gelucire1 44/14 PEG 400 (6:1) based solution. The investigators attributed the absence of crystallization of the compound in the softgels containing Gelucire1 44/14 PEG 400 (6:1) based ll to minimal migration of water from the shell into the ll. Indeed, the reported water contents of the ll and the shell at equilibrium were 6.4 0.1% and 9.6 0.2%, respectively for the PEG 400 based ll versus 1.1 0% and 5.6 0.1%, respectively, for the Gelucire1 44/14 PEG 400 based ll. Propylene glycol, due to its lower viscosity and higher plasticizing efcacy for gelatin, requires lower water content in the production the gel mass compared to glycerin or sorbitol as the plasticizer. The initial lower water content of the shell formulation containing propylene glycol as the plasticizer may also have the advantage
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of a comparatively smaller amount of water migration into the ll that could potentially minimize the precipitation of sparingly water soluble compounds in the ll.37 Thus, the extent of water migration within the softgel and ultimate physical stability of a softgel product can be controlled through the careful selection of a suitable solubilizing vehicle as the ll and a suitable plasticizer in the shell. Water migration from the shell into a lipid ll, though in minute amounts compared to polyethylene glycol based lls, may still have profound consequences on the solubility of some compounds in lipid vehicles.252254 The presence of water in a lipid vehicle may alter the solubility of a compound by one of three ways: (a) via disruption of hydrogen bonding between the molecules of the lipid and those of the solubilized compound and thereby reducing the solubility if this hydrogen bonding is a major driving force for the solubilization of the compound in the lipid;252 (b) via inducing reorganization of the lipid molecules within the matrix from the original molecular arrangement existed in the absence of water;254 and/or (c) via formation of a hydrate of the dissolved compound having reduced lipid solubility.253 Land et al.,253 for example, have shown that the presence of even ultra-low water content in the lipids was sufcient to induce hydrate formation and reduce the lipid solubility of compounds, such as anhydrous testosterone. Deterioration of Mechanical Strength of Shell Polyethylene glycols of a lower molecular weight ( 400D), used as ll vehicles, have a higher afnity for water and glycerin used in the shell formulation, leading to the migration of these shell components into the polyethylene glycol ll. The migration of water from the shell into a polyethylene glycol ll may be reduced to some extent by the use of a higher molecular weight polyethylene glycol that has a lower hygroscopicity, for example, substituting PEG 600 for PEG 400. Migration of a plasticizer from the shell into the ll in a softgel could result in the reduced elasticity (exibility) and increased brittleness of the shell shortly after production or on storage, especially when exposed to cold temperatures.40,41,255 The elasticity of the shell in such a case could be markedly improved by the inclusion of a small amount of glycerin in the polyethylene glycol ll.255 The improvement in the elasticity of the softgel shell containing the encapsulated PEG 400 ll with the added glycerin (or propylene glycol) was attributed to the equilibration of glycerin between the shell and the ll, resulting in the reduced migration of the plasticizer from the shell into the ll. Substitution of a portion of glycerin with partially dehydrated sorbitol (Sorbitol Special) as a plasticizer was also
shown to provide some marginal improvement in the elasticity to the shell containing the encapsulated PEG 400 ll without the added glycerin on aging. In contrast, it was shown that the incorporation of or migration of increasing amounts of PEG 400 into the shell containing glycerin or sorbitol as the plasticizer reduced its elasticity and increased its brittleness.255 It was speculated that the increased PEG 400 concentration in the shell may induce migration of glycerin from the shell into the ll when glycerin was the plasticizer and incompatibility between PEG 400 and sorbitol within the shell due to their immiscibility when sorbitol was the plasticizer. Chemical Stability Reactions between Encapsulated Compounds and Excipients Compounds containing reactive moieties in their structures have known to react with hydroxyl compounds used in softgels either as solvents, plasticizers, or to meet other functional requirements (e.g., polyethylene glycols, propylene glycol, glycerin, sorbitol, or their partial esters), resulting in the formation of esters, carbonates, and amides.100,256260 Though these reaction products may be ultimately hydrolyzed back to their parent compounds in the GIT, the bioavailabilities of the parent compounds could be reduced signicantly.259,261,262 The rate and extent of these reactions between an encapsulated compound (or its degradation product) and a hydroxyl component in a softgel are inuenced by (a) intrinsic chemical reactivity of the compound, (b) state and extent of ionization of the compound, (c) hydroxyl content of the solvent, (d) water content of the ll, (e) manufacturing conditions, and (f) storage conditions. The ionized form of a carboxylic acid compound, such as ibuprofen, (R-COO) is relatively less reactive towards a hydroxyl compound compared to its unionized form (R-COOH).100 In addition, as esterication and hydrolytic reactions are generally reversible, hydrolysis of the formed esters back to the parent compounds could be potentially achieved through increasing the amount of available water in the ll formulation. Thus, the rate and extent of degradation (i.e., esterication) of a carboxylic acid compound in the presence of a hydroxyl compound can be reduced through partial ionization of the carboxylic acid groups (complete ionization, though further reduces the esterication reaction, also reduces the enhanced solubilization advantage gained by using a counter ion technique, as discussed in Solubility Enhancers for Hydrophilic Vehicles Section), reduction in the amount of available hydroxyl content (i.e., use of a lower amount of a hydroxyl solvent or use of a solvent with lower hydroxyl content, e.g., use of PEG 600 instead of PEG
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400 or MPEG instead of PEG), increase in the amount of available water in the softgel, and use of milder manufacturing conditions.98,100,258 The decomposition of aspirin in polyethylene glycols in the absence of water was also attributed to the transesterication reactions, resulting in the formation of salicylic acid and acetylated polyethylene glycols.256,257,263 These transesterication reactions were shown to be affected by temperature (rate at 608C > 458C > 278C > 48C) and the number of hydroxyl reactive sites available on the polymer chain (rate in PEG > methoxyPEG > PEG acetate). Compounds encapsulated in softgels could potentially undergo hydrolytic degradation during the shelf-life of a product as a result of migration of water from the shell into the ll. During the softgel formulation development for a poorly water soluble investigational compound, VX-497, solubilized in PEG 400, Kochling et al.260 demonstrated the hydrolysis of urea bonds in the compound even at storage temperatures as low as 58C. The hydrolytic degradation of the compound in PEG 400 vehicle was attributed to the moisture content of the ll, reported to be about 7%. The investigators also demonstrated how reactions between PEG 400 and the urea carbonyl groups present in the compound and in its structurally related process impurity could result in the formation of a series of PEGylated compounds. The PEGylation reactions of the compound and its process impurity with PEG 400 were shown to be temperature and time dependent, that is, the higher the manufacturing process temperature and the longer the mixing time, the greater the concentrations of these PEGylated products. In this case, the rate of degradation of the compound (i.e., PEGylation) was successfully reduced and the overall quality of the drug product was improved through removal of the process impurity during the manufacture of the drug substance, and lowering of the manufacturing temperature and shortening of the mixing time during the manufacture of the drug product. Autooxidation of Excipients and Affects on Stability of Encapsulated Compounds Polyethylene glycols and materials containing polyoxyethylene moieties in their structures are known to undergo autooxidation in the presence of oxygen and produce reactive organic peroxides and hydrogen peroxide.95,213218,264268 The organic peroxides are further degraded to produce short chain carboxylic acids and aldehydes. It has been postulated that polyoxyethylene moieties undergo oxidative decomposition at high temperatures in the presence of water to ethylene glycol, which may then be oxidized further to form formaldehyde.269 The amounts of these reactive peroxides, carboxylic acids, and aldehydes
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present in a polyethylene glycol or in a related material are dependent upon the molecular weight and age of the polymer and the extent of its exposure to air during its storage.214,267,270 The higher the molecular weight of the polymer, the lower the concentrations of these products and the older the polymer, the greater the concentrations of these products. The relatively higher levels of these products observed in a polyoxyethylene polymer of a lower molecular weight may be related to the increase in the mobility of the polymer chains allowing for the increased autooxidation reactions.267 The reactive products generated from the autooxidation of polyoxyethylene polymers have been implicated in the degradation of several compounds formulated in polyethylene glycols.95,215,218,269,271 The carboxylic acids so formed during the autooxidation reactions could lower the apparent pH of an aqueous polyethylene glycol solution, the extent of which is dependent upon how much autooxidation of polyethylene glycol might have taken place during its handling and storage.218 The lowered pH can degrade compounds that are susceptible to hydrolytic degradation under acidic conditions.95 On the other hand, the reactive aldehydes can cross-link compounds containing amino groups in their structures through methylene groups.95,272274 The mechanism of these cross-linking reactions is similar to the methylene bonding between two amino groups on adjacent gelatin chains, as described in an earlier section. The autooxidation reactions in polyethylene glycols and their related materials and the formation of reactive products resulting from these reactions can be minimized effectively by the use of an antioxidant in the ll formulation, purging the formulation with nitrogen during its manufacturing, and thoroughly deaerating the formulation under vacuum before its encapsulation into softgels.215,218 In addition to polyethylene glycols and their related materials, peroxide and aldehyde impurities are also known to present in other excipients and packaging components used with the softgel products.219,220,268,275278 The peroxide impurities in povidone, a typically used solubility enhancer and viscosiers in softgels,55,56,67,98 are known to promote signicant degradation of oxidatively sensitive compounds even in solid-state (e.g., degradation of raloxifene to its N-oxide in tablet formulations containing povidone as an excipient277). These peroxides are present in povidone initially as process impurities and are known to increase in content with time in the presence of atmospheric oxygen.279 Formaldehyde, a known contaminant in packaging material, was shown to degrade ropinirole to its hydroxymethyl adduct.276 Equally important, the minor impurities present in a gelatin shell, for example, ammonia resiJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 10, OCTOBER 2010
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due resulting from the amide hydrolysis of asparagine and glutamine residues during the acid or alkaline hydrolysis of collagen, could also potentially induce degradation of encapsulated compounds.280 The degradation of such encapsulated compound can be minimized through the use of gelatin with reduced ammonia content. A thorough understanding of these reactions and their effects on the stability of encapsulated compounds is essential in improving the quality of a softgel product. Migration of Solutes between Fill and Shell Components Softgels, due to their very dynamic nature, could potentially give way to considerable migration (partitioning) of solutes between a shell and an encapsulated ll.60,183,281,282 The extent of migration of a solute between a ll and a shell depends on the hydrophilicity of the solute, composition of the shell formulation (e.g., type and concentration of plasticizer), nature of the ll vehicle, and the conditions to which the softgel product is subjected to during its manufacturing and shelf-life. Compounds with higher aqueous solubility can preferentially migrate from an encapsulated ll into a hydrophilic shell. In contrast, lipophilic compounds migrate from a ll to a shell to a lesser extent. Investigations by Armstrong et al.281 on the migration of compounds of varying aqueous solubilities from a ll into a shell suggested that the rate and extent of migration of the compounds followed the same rank order as their aqueous solubilities, but had no relationship to the solubilities of these compounds in the ll vehicle. Interestingly, most of the solute migration appeared to take place during the tumble drying process (primary drying process), followed by tray drying process (secondary drying process). The larger extent of migration of a solute during the drying processes may be the result of either diffusion of water from the ll into the shell and then out, carrying out the hydrophilic solute in the process or higher water content and lower viscosity of the shell material before the completion of drying processes that would favor the partitioning of the hydrophilic solute into the shell. During the migration process, some of the solute may further migrate to the outer surface of the softgel shell, from which it could be eroded by friction, or else removed by washing.281 Ethyl alcohol, a cosolvent commonly used in SEDDS and SMEDDS, is another example of a ll component that was also shown to diffuse readily through the conventional softgel shells at such a rate that most of ethyl alcohol would have disappeared from the ll by the end of the drying processes.60,183 Loss of ethyl alcohol from an encapsulated ll could potentially result in the precipitation of a dissolved compound, especially when the cosolvent is used to maintain the compound in solution.283 The migration
or loss of any critical component present in the SEDDS and SMEDDS ll formulations could also have a signicant negative impact on the in vitro and in vivo performance of these formulations.37,284 On the other hand, a shell material containing encapsulated acid salts, mineral acids, and organic acids may be at the potential risk of acid hydrolysis of the polypeptide chains in gelatin due to the migration these compounds into the shell.143,161,281,285 The loss of a volatile component from a ll formulation can be minimized, though not completely avoided, by packaging the softgel product in a solvent tight packaging material, such as an aluminumaluminum blister (Fig. 7).59 Other ways to overcome the problem is the use of a nonvolatile cosolvent that is not susceptible to any diffusion into and across the capsule shell.37,59,286 A variety of nonvolatile cosolvents have been investigated to substitute ethyl alcohol in the preparation of SEDDS and SMEDDS for softgel encapsulation, including propylene glycol, diethyleneglycol monoethyl ether (Transcutol1), tetrahydrofurfurylalcohol polyethylene glycol (Glycofurol);283,287 propylene carbonate, mixture of propylene carbonate and polyoxyethylenepolyoxypropylene block copolymers;59,104 dimethylisosorbide;288 and ethyl lactate.104 SEDDS and SMEDDDS containing a lipophilic cosolvent (e.g., triacetin, triethyl citrate, acetyltriethyl citrate) instead of a hydrophilic cosolvent have also been discussed in the literature.104,286 Cosolvents of a lower viscosity are usually preferred to those of a higher viscosity in the preparation of SEDDS and SMEDDS as the use of the former may
Figure 7. Loss of ethyl alcohol cosolvent from softgels containing a cyclosporin SMEDDS ll formulation (~) packaged in bottles, stored at RT; (*) packaged in bottles, stored at 358C/75%RH; (^) packaged in aluminum foil, stored at RT; (&) packaged in aluminum foil, stored at 358C/75%RH (adopted from Kim et al.59).
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be better able to promote emulsication with minimal effort.
ALTERNATE DELIVERY STRATEGIES FOR NONAQUEOUS FORMULATIONS

Softgel delivery system offers the advantage of conveniently delivering a nonaqueous liquid or semi-solid matrix containing a dissolved or dispersed compound as a unit dose solid dosage form. However, a variety of factors may inuence the decision making process of an organization in the development and introduction of a compound into commercialization as a softgel product. These factors may be strategic or technical and worth further discussion: (1) Manufacture of softgels is inherently a very complex, labor-intensive, and time consuming process that requires not only acquiring and maintaining specialized and costly equipment, such as gel reactors, encapsulation machines, dyes, tumble dryers, and drying tunnels but also in-house technical and operational expertise and sourcing high quality gelatin. As a consequence, organizations are reluctant to set up their own softgel manufacturing operation in-house and prefer to outsource the activities to an external softgel contract manufacturer. (2) Due to the availability of only few contract manufacturing organizations (CMOs) that specialize in the manufacture of pharmaceutical quality softgel products (e.g., Pharmaceutics International, Inc., Banner Pharmacaps, Inc., Catalent Pharma Solutions, Accucaps Industries Ltd, Pharmagel Engineering SPA), lengthy product development and manufacturing lead timelines are not unusual at the CMOs. (3) Availability of limited quantities of a compound during the early stages of development may discourage an organization from developing a softgel product for the compound as an early stage clinical dosage form. (4) Intellectual property (IP) rights of a CMO on the composition of a shell formulation may complicate issues related to transferring and manufacturing the softgel product at an alternate CMO, especially when a specialized shell composition is used in the product. (5) Technically, the high initial water content of the shell formulation at the time of encapsulation and subsequent migration of any amount of water between the shell and the ll formulations could make the softgel dosage form unsuitable for encapsulating compounds that are
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prone to water induced crystallization or hydrolytic degradation. (6) Even after an organization chooses to initiate development and commercialization of a compound as a softgel product with improved bioavailability as the rst-line introductory dosage form, the relatively higher production costs compared to those of some other dosage forms, formulation/excipient related issues, and/or some other aforementioned issues would encourage the organization to pursue an alternate dosage form at a later stage. Some examples of such fruitions include reformulation of Agenerase1 softgel into Lexiva1 tablet containing a prodrug of the compound (GlaxoSmithKline), reformulation of Fortovase1 softgel into Invirase1 tablet and capsule containing the mesylate salt of the compound (Roche Pharmaceuticals), and reformulation of Kaletra1 softgel into tablet with increased drug loading, improved stability, lowered restrictions on storage conditions, and reduced food effects (Abbott Laboratories). On the other hand, some compounds that were originally introduced into commercialization as a conventional tablet or capsule dosage form were reformulated into softgels as a part of an organizations life-cycle management strategy or some other reason (e.g., Hytrin1, Abbott Laboratories; Claritin1, Schering-Plough). Some softgel products (e.g., Zantac1, GlaxoSmithKline) were withdrawn from the market entirely as they offered no additional advantage over the tablet formulations. Some additional information on the reformulation efforts of other softgels are presented in Table 2.
When formulation of a compound in a nonaqueous vehicle is shown to be the practical option to achieve its acceptable bioavailability (e.g., Neoral1), dictated by its physical nature (i.e., low melting point, oily, waxy) (e.g., Depakene1), and/or dictated by its ultralow to low dose requirements (e.g., Rocaltrol1), the probable solid oral dosage form that has good patient acceptability is the capsule.289 Hard gelatin capsule (HGC) dosage form has been advanced as an alternate to softgel dosage form for encapsulating nonaqueous liquid and semisolid formulations.289296 There are substantial differences between the two types gelatin capsules and each dosage form has been shown to have its own advantages and challenges. The choice of soft gelatin or hard gelatin capsule for encapsulating liquids will depend on a variety of factors that will be discussed later. First of all, it is useful to discuss briey how a formulation scientist can strategize various options creatively to overcome some of
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the challenges posed by the softgel dosage form development. It is a reasonable approach to separate the softgel dosage form development into two stages: (1) development of softgel compatible ll formulation inhouse using knowledge provided in the current manuscript and other literature and (2) encapsulation and scale-up manufacturing of the softgel product at a CMO using a gel mass of composition commonly used across various softgel manufacturers. This approach allows an organization to develop the ll formulation in-house with smaller quantities of the compound, keep control of its formulation, process, and IP, and also offers the exibility of manufacturing the nal softgel product at more than a single manufacturer. Another advantage of this approach is that the ll formulation so developed can be packaged as a Liquid-In-Bottle (LIB) product and used to advance the early phases of a clinical program by either encapsulating the liquid into two-piece hard gelatin capsule (Liquid-In-Capsule, LIC) or dispensing unit doses of the liquid into individual containers for dilution with a compatible vehicle before use.297 The organization can, in the interim, develop an alternate dosage form, if feasible, evaluate the option of further development of liquid lled hard gelatin capsule (HGC) dosage form, or select softgel CMOs and negotiate contracts, if softgel dosage form is the only practical option for the compound and to further advance the clinical program. Koon298 has provided some additional tips on selecting a suitable softgel contract manufacturer. When formulation of a compound in a nonaqueous vehicle is shown to be the only practical option, the choice to continue with liquid lled HGCs or switch to softgels for later stage development and subsequent commercialization is generally determined by two factors. Dosage form related: (a) tolerance of capsule shell towards the ll composition (i.e., hydrophilic or lipophilic, type and amount of PEG and cosolvents, amount of water) and (b) tolerance of ll towards the shell water content (i.e., crystallization and/or hydrolytic degradation of an encapsulated compound). Encapsulation related: (a) existing in-house development and manufacturing capabilities and personnel expertise and (b) ease and cost of setting capabilities and improving personnel expertise. Empty hard gelatin capsule (HGC) shells are manufactured separately and supplied for encapsulating either a powder ll or a liquid ll. HGC shells are generally thinner and lighter than those of softgels and are commonly manufactured from gelatin, water, a colorant(s), and/or an opacier. HGC shells, unlike those of softgels, do not contain a nonvolatile plasticizer (e.g., glycerin, sorbitol) and
thus presence of water in the shells is essential to maintain their integrity. HGC shells must retain a moisture content of 1018% to maintain their exibility.299,300 Below this range, the shells become brittle and are prone to breakage, while above this range, the shells may deform. Thus, any alteration to this moisture range, due to migration of moisture between the shell and encapsulated ll or between the shell and external environment, could be detrimental to the integrity of the HGC shells. In contrast, the presence of plasticizer(s) in the softgel shell imparts elasticity to the shell that allows it to accommodate a wide range of hydrophilic excipients. For example, polyethylene glycols with molecular weight as low as 400 which are hydrophilic have been successfully encapsulated into softgels (Tab. 2), whereas HGC shells have been reported to be compatible with polyethylene glycols with molecular weight higher than 4000.289,296,301 Water and highly hygroscopic excipients, such as glycerin, sorbitol, propylene glycol, have also been reported to be incompatible with the HGC shells at concentrations as low as 5%.291,296 Furthermore, the relatively higher elasticity of the softgel shell resulting from the presence of a plasticizer would also provide additional protection to the softgel product during its handling. On the other hand, due to the substantially lower water content of the HGC shells, its migration into the ll would be insignicant and thus prevent or minimize any water induced crystallization or hydrolytic degradation of the dissolved compound encapsulated in the HGC. A softgel is a one-piece, hermetically sealed shell capsule, which is formed, lled entirely with no headspace, and sealed in one operation. In case of HGCs, the body of the capsule is lled, capped, and sealed sequentially, leaving substantial headspace within !10% of capsule volume.292,302 The presence of the headspace within the HGCs may compromise the elegance of a product designed with a transparent shell formulation and the oxidative stability of an encapsulated compound. The loss of llable volume in a HGC may also result in a relatively larger capsule size compared to that of a softgel containing a similar ll volume. As empty HGC shells are supplied ready for use with various ll volumes292,302 and laboratory scale equipment is also readily available for lling and sealing HGCs,292,295,302 small scale batches of a liquid lled HGC product can be easily manufactured inhouse using small quantities of a compound for stability and clinical trial purposes during the early stages of drug development. In fact, based on the authors experience, these small scale batches can also be manufactured easily using simple equipment, such as a ProFillTM Capsule Filling system (Torpac, Inc. http://www.torpac.com/) and a positive displaceDOI 10.1002/jps
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Table 5. Small Scale Softgel Encapsulation Machines

Machine Designation R&D 4 inch RGY6x15F, RGY6x15S PSG-100 SS-30 RG0.8-110
a
Supplier CapPlus Technologies (Phoenix, AZ) Pharmaker Machinery (Elmont, NY) Pharmaland Technology (Ontario, Canada) Sky Softgel Co. (Incheon, Korea) Zhejiang Fuchang Machinery Co. (Zhejiang Province, China)
Die Roll Specicationsa Max. die speed 5 rpm, die rolls 4 inch long 2.83 inch diameter Max. die speed 4 rpm, die rolls 3.94 inch long 2.52 inch diameter Max. die speed 5 rpm, die rolls 3.94 inch long 2.56 inch diameter Max. die speed 5 rpm Max. die speed 7 rpm, die rolls 4.33 inch long 2.83 inch diameter
Output depends on softgel size and number of cavities and rpm of die roll.
ment pipette. Moreover, unlike softgel manufacturing, as there is no need for a time consuming gel mass preparation and capsule drying process, liquid lled and sealed HGCs can be manufactured and packaged within a short time. The readers are directed to the literature published by Cole et al.,289 Cole,292 Smith,295 and Rowley303 to obtain any further understanding of the manufacturing process for the liquid lled HGCs and their characteristics. R&D scale softgel manufacturing machines have also been introduced for the production of softgels at a smaller scale. Some of these machines are commercially available and offer an organization with the option to keep its softgel development and manufacturing activities in-house. Some of the softgel encapsulation machines available commercially are presented in Table 5. A laboratory scale encapsulation machine (Minicap) mimicking the design of a standard softgel encapsulation machine, but utilizing a single pocket die design and requiring as little as 50 mL of ll solution has been discussed in the literature.304 The Minicap has been shown to produce softgels with comparable qualities as those manufactured using a standard softgel machine and thus can be used to produce prototype softgels for ll-shell compatibility screening and stability evaluation. However, the Minicap machine, developed by Cardinal Health (currently Catalent Pharma Solutions), may not be available for purchase. Though softgel manufacturing machines and auxiliary equipment are readily available for purchase, due to enormous resources required, for example, designing facilities, sourcing and controlling qualities of gelatin, optimizing manufacturing process for gel mass, acquiring and developing in-house talent and so on, an organization has to carefully evaluate the option of establishing softgel manufacturing capabilities in-house against outsourcing and managing the outsourced activities. It is also essential to bear in mind that the major CMOs that specialize in the manufacture of softgels have their own in-house machine shop capabilities that can build, replace,
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and/or repair any existing machine parts right away with minimal loss of time.
CONCLUSIONS
Softgels constitute a unique solid dosage form that can be used to conveniently encapsulate nonaqueous solution, suspension, and semisolid formulations developed to improve the bioavailability of poorly soluble compounds. In addition to several softgel products that are already available commercially, the patent literature and the number of softgel products currently under clinical investigations305 clearly demonstrate that several pharmaceutical and biotech rms are actively pursuing the softgel dosage form as a choice to formulate compounds with poor biopharmaceutical properties. The potential of the softgel dosage form in improving the in vitro and in vivo performance and the physical and chemical stability of an encapsulated compound can be maximized through the careful selection of appropriate excipients in the ll and shell formulations. While the dosage form provides immense promise for a variety of poorly soluble compounds, its dynamic nature compels the formulation scientist to put in more efforts than during the development of other conventional solid dosage forms, such as tablets and two-piece hard gelatin capsules. The potential risks that may arise during the development and shelf-life of a softgel product can be managed through the use of: a stable physical form of the drug substance, a ll vehicle that minimizes the transfer of water from the shell into the ll and/or lessens the effect migrated water on the solubilized state of the drug substance, excipients free from interactions with the drug substance and/or with each other, excipients free from impurities (e.g., aldehydes, peroxides) that may adversely effect the gelatin
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shell dissolution process and/or the chemical stability of the drug substance, plasticizer(s) that minimizes the transfer of components from the ll (e.g., ethyl alcohol) or into the ll (e.g., oxygen, moisture), inert environment during manufacturing, for example, nitrogen blanketing for oxygen sensitive compounds, yellow light for photosensitive compounds, thorough deaeration of the ll formulation to remove any dissolved air (oxygen), moderate drying conditions, and appropriate storage conditions, that is, container/ closure, temperature, and relative humidity.
Finally, softgels may not be the appropriate dosage form for some compounds that are highly moisture sensitive or have high therapeutic dose requirements, and alternate dosage forms may be more desirable and cost- and time-effective in such a case.
ACKNOWLEDGMENTS
The author thanks the Library Staff at Elan Pharmaceuticals, Ms. Nancy Phelps, Mr. Cary Cochrell, and Ms. Praveena Raman, for their help in collecting relevant literature to complete the manuscript. The lans IT department for author also thanks Staff of E their assistance in the preparation of gures.
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