PRE-FORMULATION AND FORMULATION

OF SOLID DOSAGE FORMS

RESEARCH AND DEVELOPMENT

Assoc.Prof.Dr. Kampanart Huanbutta

OBJECTIVES
Understanding of pre-formulation process for solid dosage
forms
Understanding R and D process of solid dosage forms
formulation, especially tablet
Can plan for formulation of solid dosage form unit
Can plan for stability test
Can calculate Similarity factor
OUTLINE
Introduction
Pre-formulation
Process of formulation
Stability testing
REVIEW OF SOLID DOSAGE FORMS
How many types
Excipients
Preparation
Evaluations
TABLET
Plain tablet
Coated tablet
Buccal or sublingual tablet
Effervescent tablet
Chewable tablet
Controlled drug released tablet
 PLAIN TABLET
Most common dosage forms
Transportation
Might hide the unpleasant taste
Smooth tablet easy to swallow
Stability
Shelf life
CAPSULES
Simple preparation process
Use low amount of excipient
Medication in gelatin container
Taste masking
Type
Hard-shelled capsules: for powder
Soft-shelled capsules: for oil and liquid ingredient
GRANULES
Solid, dry aggregates of powder
Might directly apply or dissolve in water before use
(might be effervescent granules)
Advantage
Stability
Flow
Dissolution rate
POWDERS (ORAL)
Bulk powders
Usually non-potent medicine
Use only necessary excipient: coloring agent
Use: disperse/dissolve in water
Divided powder
Single dose
Small sachet
PRODUCT LIFE CYCLE

Formulation
development

Ref: Gibson, M. (2001). Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, Taylor & Francis.
OBJECTIVE OF FORMULATION

Establish optimum manufacturing parameter

Minimize batch to batch variation
Provide scientific justification for processing
parameters / ranges
 PREFERRED PHARMACEUTICAL PROPERTIES FOR COMPOUNDS
INTENDED FOR ORAL SOLID DOSAGE FORM DEVELOPMENT

Formulation/Drug Delivery Factors

Exists as a stable polymorphic form
Non-hygroscopic
Crystalline
Acceptable solid-state stability of candidate drug

Acceptable oral bioavailability

* to ensure batch reproducibility
Not highly coloured or strong odour * and reduce problems with
blinding in clinical studies)
Compatible with key excipients
PROTOTYPE FORMULATION DEVELOPMENT
Pre-formulation
Finding information (from paper
and experiment) of API and
interested excipients
Principal areas of pre-formulation
Bulk characterization
Solubility analysis Analytical Profiles of Drug Substances

Stability Analysis
 PRINCIPAL AREAS OF PRE-FORMULATION
1. Bulk characterization 3. Stability Analysis
Crystallinity and polymorphism (i) Stability in toxicology formulation
(ii) Hygroscopicity (ii) Solution stability pH stability profile
(iii) Solid state stability Bulk stability Compatibility
(iii) Fine particle characterizatio
n
(iv) Powder flow
2. Solubility analysis
Formulation Approach Place on prototype
- Excipient compatibility stability
(i) Ionization constant pKa
- Develop 2 - 3 prototype 1. Evaluate physical
(ii) pH solubility profile
formulations and chemical
(iii) Common ion effect K SP
- Wet granulation 2. Evaluate pH
(iv) Thermal effects
- Direct compression dependency of
(v) Solubilization
- Roller compaction (dry release rate
(vi) Partition coefficient
granulation)
(vii) Dissolution
PREFORMULATION STUDIES
Physical Description
Microscopic Examination
raw drug substance

Heat of Vaporization
important in the operation of implantable pumps delivering medications as well as in
aerosol dosage forms
Melting Point Depression
Check purity and identification

The Phase Rule

Triangular Phase Diagram
TABLET FORMULATION DEVELOPMENT OUTLINE

Prototype formulation
1. 250-500 g per bath size
- Pivotal Bioequivalence
Scale up to pilot scale - Registration Batch
15 kg - Manufacture
2. Try real process/formulation DOE Technology Transfer
Pivotal scale up
3 More than 10% of commercial scale
EQUIPMENT
Equipment type and mechanism should be the same with
production line
R and D has smaller size of manufacturing equipment
Mixing time
Drying time
Binder amount
Tableting parameter
Contamination
Cost
LATE PHASE DEVELOPMENT
FORMULATION DEVELOPMENT
Pre-
formulation

Formulation Method
development development

Select Vary setting

Select
Vary portion proper parameter
excipient
method (instrument)
FACTORS TO BE STUDIED (INSTRUMENT/PROCESS OPERATION)

High shear wet granulation Blender

Spray rate Blending time
Granulating fluid use
Type and volume
Impeller shopper speed
Speed

Fluid bed dry Compression

Inlet temp Force (upper/lower punch setting )
Dew point Speed
Shape of punch

Sizing Coating
Feed rate Spray rate
Screen size Pan speed
Mill speed Inlet Temp
Wet or Dry
WHAT SHOULD WE CHECK
Wet granule Dry granule bulk and tap density
Granule size / shape distribution
Flow indicators (flow rate)
Granulation moisture content (LOD)
Tablet weight, thickness, hardness, disintegration, friability,
dissolution
Content uniformity
 EVALUATE FORMULATION
API load
High API load with good
properties good formulation
Ratio of excipients
Hardness vs. force DT
Granulation particle size Weight
variation
Friability excipient and process
Dissolution Profile Similarity

API physical characteristics

Temp, light, moisture
Flow properties
Granule/ adding excipient
 SIMILARITY FACTOR
Similarity factor (f2)
dissolution
profiles


Difference factor (f1)
2
curves

(relative error)
2 curves
F1 AND F2
F1 around 0-15
F2 in range of 50-100
PLEASE CALCULATE AND GIVE THE RESULT OF F1 AND F2
 DRUG STABILITY: MECHANISMS OF DEGRADATION
1. Chemical: Each active ingredient retains its chemical
integrity and labeled potency within the specified limits. Storage conditions (temperature,
2. Physical: The original physical properties, including
light, humidity),
appearance, palatability, uniformity, dissolution, and selecting the proper container for
suspendability are retained. dispensing (glass vs. plastic, clear vs.
amber or opaque, cap liners)
3. Microbiologic: Sterility or resistance to microbial
growth is retained according to the specified
requirements. Antimicrobial agents retain effectiveness
within specified limits.
4. Therapeutic: The therapeutic effect remains
unchanged.
5. Toxicologic: No significant increase in toxicity occurs.
cap liners
DRUGS THAT SHOULD BE CAREFUL WITH THEIR
EXPIRATION DATE
Anticonvulsants - narrow therapeutic index
Dilantin, phenobarbital - very quickly lose potency
Nitroglycerin - very quickly lose potency
Warfarin - narrow therapeutic index
Procan SR - sustained release procainamide
Theophylline - very quickly lose potency
Digoxin - narrow therapeutic index
Thyroid preparations
Paraldehyde
Oral contraceptives
STABILITY TESTING
Accelerated storage condition
Stress condition
Find degradation kinetics
40 C 2 C, RH 5 % RH

Real time storage condition

Confirm drug quality and quantity
during on the shelf
30 C 2 C RH 5 % RH
Sampling time
0, 3, 6, 9, 12, 18 and 24 month
And every year until expire

For solid dosage form, keep in tight container Stability chamber

 TESTING TOPIC
Chemical test

API Content
Amount of Preservative and/or Antioxidant
Impurity and Degradation product
Microbial Limit Test
Every 6 month in stress condition
Every year for real condition
Physical Test
Depend on dosage forms
Appearance, Odor, Color test, pH,Viscosity, % Water content, Dissolution, Disintegration time,
Hardness, Friability, Deliverable volume, Particulate matter
ASSIGNMENT

R and D solid
dosage forms

4 2560 18.00
( 80 ) google doc ( public
view only)

-

pre-formulation
innovator


3-5
scale up


finish product
stability test