TSF Steril Pertemuan 7-1

1
Teknologi Farmasi Steril

Rumpun Teknologi Farmasi
Nurfitriyana, M.Farm., Apt
Institut Sains & Teknologi Al-Kamal

Genap 2021/2022
2
Pertemuan 7
Eksipien dalam Sediaan Steril
POKOK BAHASAN
• Eksipien
• Karakteristik Eksipien
• Tujuan Penggunaan Eksipien
• Manfaat Penggunaan Eksipien
• Jenis Sediaan Farmasi Steril
• Karakteristik Sediaan Farmasi Steril
• Tujuan Penggunaan Eksipien pada
Sediaan Farmasi Steril
• Komponen Eksipien dalam Sediaan
Farmasi Steril
4
Principle
Parenteral drugs are formulated as
solutions, suspensions, emulsions,
liposomes, microspheres, nanosystems, and
powders to be reconstituted as solutions.
5
6
Components of parenterals
• Active pharmaceutical ingredients
• Vehicle
• Added substances
• Primary container
• Closure
Eksipien
• Eksipien adalah zat yang digunakan
sebagai bahan tambahan/ pendukung
suatu formula sediaan, bersifat inert dan
tidak memiliki efek farmakologi
Karakteristik Eksipien yang
Baik
• Inert
• Stabil secara fisik dan kimia
• Bebas mikroorganisme patogen
• Dapat mendukung bioavaibilitas
• Tersedia dalam perdagangan
• Harganya terjangkau
• Biokompatibel
• Kompatibel dengan Obat dan Eksipien
lainnya
• Kompatibel dengan Pengemas
Tujuan Penggunaan Eksipien
• Bahan pembantu selama proses
pembuatan sediaan berlangsung
• Mencegah, mendukung atau
meningkatkan stabilitas dan
bioavaibilitas
• Membantu identifikasi produk
• Meningkatkan keamanan, efektivitas
produk obat selama penyimpanan atau
penggunaan
Manfaat Penggunaan Eksipien
• Dapat memberi nilai tambah pada sediaan
▫ Lebih stabil secara fisik dan kimia
▫ Memperbaiki tampilan fisik
▫ Mempengaruhi sifat lepasnya obat
• Oleh sebab itu mendesain suatu sediaan
perlu pengetahuan mengenai eksipien
yang digunakan dalam formula agar
dihasilkan produk yang bermutu, aman,
menarik dan memberikan efek terapi
yang diinginkan
Sediaan Sediaan
Parenteral Parenteral
Volume Volume
Besar Kecil
Sediaan
Sediaan
Nasal dan
Oftalmik
Otik
Karakteristik
Penggunaan eksipien harus dapat mendukung pembuatan

sediaan farmasi steril yang memiliki 7 karakteristik dasar
sediaan farmasi steril
Eksipien Sediaan Farmasi Steril
Sediaan Sediaan
Parenteral Parenteral
Volume Volume
Besar Kecil
Sediaan
Sediaan
Nasal dan
Oftalmik
Otik
Tujuan Penggunaan Eksipien pada
Sediaan Steril Farmasi
• Menjaga (mempertahankan) kelarutan obat
• Menjaga Stabilitas fisika dan kimia sediaan
• Menjaga Sterilitas Sediaan
• Memudahkan pemberian obat (misalnya
parenteral dengan cara mengurangi rasa nyeri
atau iritasi pada saat penyuntikan)
Sediaan Steril Oftalmik
• Bentuk Sediaan
▫ Tetes Mata
 Larutan
 Suspensi
 Emulsi
▫ Salep Mata (Semisolid)
▫ Larutan Pencuci Mata (Kolirium)
Eksipien
• Agen Pengisotonis
• Dapar (Buffering agents)
• Pembawa (Vehicles)
• Pengawet (Antimikrobia)
• Antioksidan
• Chelating Agent
• Agen Pengental (Viscosity Agent)
• Agen Pensuspensi (Suspending Agents)
• Solubilizing and Wetting Agent
Eksipien
• Pengawet
▫ Benzalkonium Klorida
 70% digunakan untuk tetes mata
 Jangan digunakan dengan lokal anastesi
▫ Klorheksidin Asetat / Glukonat
 Bakterisidal
 Aktivitas meningkat dengan adanya aromatik
alkohol dan EDTA
 Stabil pada pH 5-6, Kurang stabil pada
proses sterilasi dengan Autoklaf
Eksipien
• Pengawet
▫ Thiomersal
 Bakteriostatik dan Fungistatik
▫ Klorbutol
 Aktif membunuh bakteri dan fungi
 Kompatibel dengan kebanyakan produk
optalmik
 Kekurangan: kurang stabil pada proses
sterilisasi dengan autoklav, volatilitas ,
mudah terabsorbi dengan wadah plastik
Eksipien
• Dapar :
▫ Buffer : Fosfat, Borat, Sitrat
• Agen Pengental:
▫ Metil selulosa
▫ Polivinil Alkohol
▫ Dektrosa
▫ NaCl
Eksipien
• Antioksidan :
▫ Physostigmine
▫ Na Metabisulfit , Na sulfit
• Chelating Agents :
▫ EDTA
• Wetting Agent and Solubilizing Agents
▫ Polysorbate 80
▫ Gliserin
▫ Propilen Glikol
Sediaan Steril Nasal dan Otik
• Telinga
▫ Tetes Telinga
▫ Bentuk Sediaan: Larutan , Suspensi
• Hidung
▫ Tetes Hidung
▫ Nasal Sprays
Eksipien
Sediaan Steril Nasal dan Otik
• Dapar
• Pengawet
• Pembawa
• Agen Pengental
• Chelating Agents
• Solubilizing Agent
• Suspending Agent
Eksipien
Sediaan Steril Nasal
• Dapar
▫ Asam Hidroklorat
▫ Potasium Sorbat
▫ Natrium Fosfat
▫ NaCl
▫ Dextrose
• Pembawa
▫ WFI
▫ Asam Oleat
• Pengawet
▫ Propyl dan Methyl Paraben
Eksipien
Sediaan Steril Nasal
• Solubilizing Agent
▫ Gliserin
▫ PEG 400
▫ EDTA
Eksipien
Sediaan Steril Otik
• Agen Pengental
• Solubilizing Agents
• Pengawet
• Pembawa (Vehicle)
• Dapar
Eksipien Sediaan Steril Otik
• Agen Pengental
▫ HEC ( Hydroxy Ethyl Cellulose)
• Solubilizing Agents
▫ Gliserin , Propylen Glycol
▫ Polysorbate 20 dan 80 ( dapat juga sebagai suspending agent)
▫ Air ,Mineral Oil
▫ NaCl
• Buffer
▫ Kalsium Karbonat , Asam Sitrat , Asam Hidroklorat , Sodium Asetat
• Pengawet
▫ Methyl Paraben
▫ Benzalkonium Klorida
▫ Benzil Alkohol
▫ Thimerosal
Eksipien Sediaan Steril Otik
▫ EDTA , Potasium Metabisulfit , Na Bisulfit
Sediaan Parenteral
• Sediaan Parenteral
▫ Infus
▫ Injeksi
▫ Serbuk untuk Injeksi
• Bentuk Sediaan Steril Parenteral
▫ Larutan
▫ Suspensi
▫ Emulsi
▫ Serbuk Kering (Dry Powder)
Eksipien Sediaan Steril
Parenteral
• Bulking Agents (u/ sediaan parenteral serbuk
injeksi)
• Lyoprotectants (u/ Sediaan parenteral serbuk
injeksi)
• Dapar (Buffering Agents)
• Agen Pengisotonis (Tonicity Adjusting Agents)
▫ Pelarut (Minyak dan Air)
▫ Solubilizing agents
• Pengawet
• Agen Pengompleks dan Pendispersi (Complexing
Parenteral
• Agen Pensuspensi (Flocculating/suspending
agents)
• Antioksidan (Antioxidant And Reducing Agents)
• Chelating agents
• Wetting Agents
• Surfaktan
• Agen Pengental
Eksipien Sediaan Steril Parenteral
• Bulking Agents
▫ Bulking agents forms the bulk of the
lyophilized product and provide an
adequate structure to the cake. These are
generally used for low dose (high potency)
drugs that do not have the necessary bulk to
support their own structure
▫ In such cases, a bulking agent is added to the
formulation matrix. The structure of the
lyophilized cake is important, since proper
cake formation leads to proper pore
formation that provides the means for vapor
to escape from the product during the drying
cycle
• Bulking Agents
• Lyoprotectants
▫ Lyoprotectant is defined as subtances used for the
stabilization and prevention of the degradation of a
molecule both during freeze-drying and afterwards,
during storage. Among disaccharides, sucrose and
trehalose appear to be the most commonly used.
▫ In comparison to sucrose, trehalose seems to be a
preferable lyoprotectant, because it has a less
hygroscopicity, very low chemical reactivity and
finally, higher glass transition temperature (Tg′) .
▫ Critical temperature is the temperature above
which the freeze-dried product loses macroscopic
structure and collapses during freeze drying.
Therefore, the excipients which provide higher
critical temperature are preferred for lyophilization
Lyoprotectants
Lyoprotectants And Bulking Comments
Agents
Manitols Mannitol has a very high eutectic
melting temperature (-1.4°C)
after crystallization and is
processed well in
lyophilization. Crystallization of
the bulking agent, however,
might adversely affect the
physical stability of the product
in certain
instances, for which, an
amorphous bulking agent is
preferred
Lactose it is a good bulking agent but is a

reducing sugar and may undergo
Maillard reaction with proteins
leading to instabilityof the
Lyoprotectants And Bulking Agents
Lyoprotectants And Bulking Comments
Agents
Sucrose It is having similar collapse
temperature i.e -31°C (2%)
as of lactose but it is not a
reducing sugar and does not
undergo
Maillard reaction . Sucrose has a
higher density as compared to
lactose which can cause slight
collapse during drying.
PEG It provides good cake structure
and increases viscosity of water
(13). The 2% solution of PEG has
a critical temperature of -22°C.
Apart from lyophilization it is
also
used as a co-solvent and viscosity
modifier in parenteral including
Lyoprotectants
Lyoprotectants Comments
Sucrose It is having similar collapse
temperature i.e -31°C (2%)
as of lactose but it is not a
reducing sugar and does not
undergo
Maillard reaction (12). Sucrose
has a higher density as compared
to
lactose which can cause slight
collapse during drying.
Polyethylene glycol (PEG) It provides good cake structure
and increases viscosity of water
(13). The 2% solution of PEG has
a critical temperature of -22°C.
Apart from lyophilization it is
also
used as a co-solvent and viscosity
modifier in parenteral including
Lyoprotectants And Bulking Agents
Lyoprotectants Comments
Polyvinyl pyrollidone (PVP) The low-molecular grades,
Povidone K 12 and K 17 are used
as solubilizing agents,
dispersants
and crystallization inhibitors,
particularly for injectables. This
application is used in particular
for antibiotics in solution or in
lyophilized form.
The povidone grades K12 and K
17 are used as solubilizers in
parenteral applications. In
addition Polyvinyl
pyrollidone also provides cryo-
protection to the product. The
C-grades are supplied with low
endotoxin levels (“pyrogen-free”)
Pengawet
• Pengawet Anti Mikrobial
Dapar ( Buffering Agents)
• Control of pH is critical to avoid degradation of
drug during processing, storage and reconstitution
• The choice of buffer depends on the pH stability
profile of active ingredient as drug needs to be
reconstituted and stored for some time before it
could be administered to the patient. For this
purpose, the pH of maximum stability of drug
should be known and maintained.
• Selection of a suitable buffer and its concentration
is important for sensitive molecules.
• The buffering agent should have a high collapse
temperature, be non-volatile and have a high glass
transition temperature (Tg).
• A high collapse temperature would facilitate a
faster primary drying, and its non-volatile nature
would prevent pH drift, that might be detrimental
to the product stability
• Commonly used buffers in the parenteral
formulations are Acetate, Citrate, Tartrate,
Phosphate,Triethanolamine (TRIS).
Agen Pengisotonis (Tonicity Adjusting Agents)
• Parenteral formulations should be isotonic with

human plasma so as to avoid damage to the tissues.
However, not all drugs at their recommended
dosage are isotonic with blood, thus requiring the
addition of a tonicity adjusting agent to the
formulation.
• The most commonly used tonicity agent is dextrose,
while others such as glycerol and sodium chloride
are less commonly used. Other commonly used
tonicity adjusting agents are: Glycerin and Mannitol
Pengawet
• Pengawet Anti Mikrobial
Pengawet Antimikobial
• Antimicrobial agents are required for parenteral products

that
are intended for multiple dosing, in order to protect the
product from
accidental microbial contamination during clinical usage &
maintain
sterility.
• Some typical preservative used in parenteral suspensions
and their commonly used concentrations are as follows:
▫ Benzyl alcohol (0.9% to 1.5%)
▫ Methylparaben (0.18%to0.2%)
▫ Propylparaben (0.02%)
▫ Benzalkonium chloride (0.01% to 0.02%)
• Agen Pengkhelat (Chelating Agents)
▫ Chelating agents are used in formulations to aid in inhibiting
free radical formation and resultant oxidation of active
ingredients caused by trace metal ions such as copper, iron,
calcium, manganese, and zinc.
▫ Ex: EDTA, Na Metabiulsfit
• Antioksidan (Antioxidants and Reducing Agents)
▫ The antioxidants and Reducing Agents are used to
prevent/minimize the oxidation reaction of the drug or
excipients over the shelf life of the product
▫ The mechanisms:
 Bind with free radical in the system
 Bind with heavy metals that contain in formula
 Prevent Reduction Oxidation Reaction
• Chelating Agent
48
• Antioksidan
Parenteral
• VEHICLE
• Solubilizing agents
• The agents which help in dissolving or increase the
drug solubility into the formulation are known as
solubilizing agents, thesolubilising agents can be
broadly classified into :
▫ surfactants : The surfactants increase the dissolution
by reducing the surface tension of the drug
substances
▫ co-solvents.: are defined as a solvent that in
conjunction with another solvent can dissolve a
solute.
• VEHICLE
• Solubilizing agents
▫ Few examples of surfactants are:
Polyoxyethylene sorbitan monooleate (Tween
80), Sorbitan monooleate Polyoxyethylene
sorbitan monolaurate (Tween 20), Lecithin,
Polyoxyethylene polyoxypropylene copolymers
(Pluronics).
▫ Examples of co-solvents are: Propylene glycol,
Glycerin, Ethanol, Polyethylene glycol (300
and 400), Sorbitol, Dimethylacetamide and
Cremophor EL etc.
• VEHICLE
• Air
• Air sbg Pembawa (VEHICLE)
• Air Air
Air Steril Air Air Steril Air steril
Untuk Injeksi Bakteriostati untuk Inhalasi untuk Irigasi
k Untuk
Injeksi
Disterilkan Ada 1 atau Disterilkan Disterilkan
Dikemas dengan lebih Agen Dimurnikan Dikemas dengan
Kontener dosis bakteriostatika secara destilasi/ dosis tunggal
tunggal kapasitas < (Benzil osmosis terbalik Tidak
1000 ml Alkohol , Metil mengandung
Paraben dan Dosis Tunggal antimikroba
Tidak Mengandung Propil Paraben) atau zat lain
Zat Bakteriostatik Tidak Kapasitas < 1ltr
Kontener mengandung
Takaran Ganda Antimikroba Untuk
membersihkan
Dikemas Untuk luka
dengan melembabkan
kapasitas < 30 udara atau alat
ml yang sama yang
• Minyak sbg Pembawa (VEHICLE)
• Minyak (Oil)
▫ Persyaratan monografi minyak untuk sediaan
injeksi ( Farmakope Edisi III)
 Minyak lemak nabati atau ester asam, lemak
tinggi alam atau sintetik dan harus jernih pada
suhu 10°C
 Bilangan Asam: 0,2< X<0,9
 Bilangan Yodium : 79 <X <128
 Bilangan Penyabunan: 185 <X <200
 Penyimpanan: Tertutup rapat, diisi penuh dan
terlindung dari cahaya
• Minyak sebagai Pembawa (VEHICLE)
• Minyak (Oil)
• Oily vehicles cannot be administered by the intravenous
route
▫ For some oil or lipid soluble drugs such as some vitamins
(Vitamin K, Vitamin E) hormons (e.g., progesterone,
testosterone, deoxycorticicosterone), oily vehicle can be
used:
 Soybean oil
 Olive oil
 Corn Oil
 Cottonseed Oil
 Sesame Oil
 Peach Oil
 Peanut Oil
• Wetting Agents
▫ Various nonionic surfactants and non-aqueous
solvents like glycerin, alcohol & propylene
glycol are types of wetting agents commonly
used in injectable suspensions.
▫ Wetting agents reduce the contact angle
between the surface of the particle & the
wetting liquid to obtain maximum wetting
efficiency; surfactants with hydrophilic
lipophilic balance (HLB) value in the range of
7to 9 should be selected.
• Wetting Agents
▫ The usual concentration of surfactants varies from
0.05% to 0.5% depending on the solid contents of the
suspension.
▫ Care should be taken in terms of the amount
used;excessive amounts may cause foaming or caking
or provide an undesirable taste/odor to the product.
▫ Surfactants (wetting agent)
 Lecithin, Polysorbate 20, Polysorbate 80, Pluronic F-68,
Sorbitan
 trioleate (span 85) are used, as surfactants in injectable
suspensions
• Wetting Agents
▫ for e.g. in the preparation of a non-aqueous
suspension of Cefazolin
 sodium in peanut oil, addition of polysorbate 80
at concentration greater than 0.17% resulted in
deflocculated suspension which was difficult to
redisperse.
 Microscopic examination revealed extensive
agglomeration and crystal growth of cefazolin
sodium in the presence of polysorbate 80
• Flocculating/suspending agents
▫ The controlled flocculation approach uses a flocculating
agent(s) to from loosely bound aggregate or flocs in a
controlled manner that settles rapidly but redisperses easily
upon agitation. An appropriate amount or flocculating agent
is added that result in maximum sedimentation volume &
prevents cake formation.
▫ Electrolytes, surfactant and hydrophilic colloids have been
typically used as flocculating agents. Electrolytes &
surfactants reduce the electrical forces of repulsion
between particles & allow the flocs to form, which in turn is
influenced by the surface charge on the particles.
• E.g. Electrolytes used in Parenteral Suspensions.
▫ Potassium/sodium chloride
▫ Potassium/sodium citrate
▫ Potassium/sodium acetate
• Flocculating/suspending agents
▫ The surface charge of the system can be measured by the
zeta potential. The zeta potential must be
controlled so as to lie within a range (generally less
than 25 mV) to obtain a flocculated,noncaking
suspension with maximum sedimentation.
▫ Hydrophilic colloids (generally negatively charged)
not only affect the repulsive force but also provide
mechanical barrier to the particles.For e.g. a 25%
PVP solution is used in combination with
polysorbate 80 (2%) acts as a stabilizer to provide a
stable injectable 30% aqueous powder suspension.
• Viscosity Agents
▫ Some viscosity building agents used in formulation of
injectable suspension are:
 Sodium carboxymethyl cellulose
 Acacia
 Gelatin
 Methyl cellulose
 Polyvinyl pyrrolidone
• Complexing and Dispersing Agents
Complexation is sometimes used to improve the solubility of
drug in the solvent especially water.
▫ Cyclodextrins have emerged as very effective additive compounds for
solubilizing hydrophobic drugs.
 In the parenteral dosage form, modified cyclodextrins, such
as hydroxypropyl-b-cyclodextrin and sulfobutylether- b –
cyclodextrin have been reported to solubilize and stabilize many
injectable drugs, including dexamethasone, estradiol, interleukin-2,
and other proteins and peptides without apparent compatibility
problems
• Terima Kasih

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Teknologi Farmasi Steril

Nurfitriyana, M.Farm., Apt

Institut Sains & Teknologi Al-Kamal

Penggunaan eksipien harus dapat mendukung pembuatan

Lactose it is a good bulking agent but is a

• Parenteral formulations should be isotonic with

• Antimicrobial agents are required for parenteral products

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