1.

Small volume (<100 ml) injectables

2. Large volume (>100ml) injectables
3. Modified release (sustained-release) injectables (SVIs
delivered by routes other than IV)
+ SVIs include solutions, suspensions, emulsions, and solids.
+ Most of SVIs are ready to use solution forms and the next
frequent type of forms are the lyophilized or powder filled
dosage forms. The third forms are suspensions, emulsions, and
other dispersed systems.
 Solutions – ready to use products or can be liquid
concentrates to be diluted in a small container or in a IV fluid.
Aqueous solutions are water based or combined with water
miscible organic solvents such as ethanol, polyethylene glycol,
glycerin or propylene glycol. Nonaqueous solutions contain
vegetable oils such as soybean, sesame, and cottonseed as
the vehicle. Oil solutions must be administered by the IV.
 Suspensions – macro- or micro-sized solids dispersed in a
suitable vehicle, water or oil. Insulin, vaccines, and
microsphere are delivered as suspensions. Suspensions are
not administered by the IV.
 Emulsions – dispersed systems combined with an oil phase and an
aqueous phase. It could be either oil-in-water emulsion or water-in-
oil emulsion, but most injectable emulsions are oil-in-water
emulsions. Liposomes are emulsified spherical vesicles composed of
a phospholipid bilayer with an aqueous inner phase. Drug can be
incorporated in either the liquid or aqueous phases. Parenteral
emulsions are milky white in appearance and have an average
globule size of 1 – 5 micrometer. Globules larger than 5 micrometer
should be less than 0.05% of the total volume. Propofol and oil
soluble vitamins are examples.
 Solids – primarily prepared by lyophilization as amorphous
solids are very difficult to fill accurately due to their lack of
density. Some solid formulation that can be crystalized and
powder filled. Sterile solids are reconstituted prior to
injection with a suitable diluent.
+ Packaged as two general types of product:

+ Large Volume Parenteral Solutions (LVP)

– Typically large bags containing large volumes of
intravenous solutions.

+ Small Volume Parenteral Solutions (SVP)

– Generally contained in ampules, vials, prefilled syringes &
piggybacks.

+ Must be sterile, free of particulate matter, pyrogen

free, because it is injected directly into the blood
stream.
+ Intravenous solutions packaged in containers
of 100mL or more.

+ Typically infused over a period of 30 to 60

minutes with the administration of LVP
solution.
+ Four solutions are commonly used as LVP
solutions or as admixtures (LVP where a drug
has been added).

– Sodium Chloride (salt)

– Dextrose Solution (sugar)
– Ringer’s Solution
– Lactated Ringer’s Solution
 LVIs include electrolytes, carbohydrates, proteins, fatty
emulsions, dialysis solutions, and irrigating solutions.
 Electrolyte solutions – 0.9% NaCl isotonic solutions, 0.45% or 3%
NaCl, 20-40 mEq/L KCl, Ringer’s lactated Ringer’s, etc.
 Carbohydrate solutions – Dextrose 5% in water (D5W)
 Nutritional proteins: 2.5 – 10% synthetic amino acid mixtures
used on patients with renal, hepatic failure or other conditions.
 Fatty Emulsions: serve as a source of nutrient fat. Composed of
10-20% soybean oil, water and 1.2% egg yolk phospholipids, and
2.5% glycerin.
 Peritoneal Dialysis: dialysis solution contains large volumes of
dextrose to remove waste such as urea and potassium from the
blood.
 Irrigating (washing) solutions – they come in various formulations
and differ from injectable solutions with the package closure.
Irrigating solutions have a screw cap that twisted open. Irrigating
solutions must be sterile, pyrogen and particulate free.
 Sustained or controlled release injectable systems are desirable
for increased duration of release, reduced number of injections,
and increased compliance, localized delivery in the case of
cancer therapy and vaccinations, and protection against in vivo
degradation of the active ingredient.
 Polymeric implants – sterile, solid drug products manufactured
by compression, melting or sintering processes. They have drug
and a biodegradable or replaceable polymeric system which
controls the sustained or prolonged drug delivery. Norplant
(birth control implant) is shown in the picture below.
 Microspheres: injectable suspensions containing particles of diameters
of 1 – 100 micrometer. Prior to injection, the particles are mixed with
an appropriate vehicle, dispersed and administered. Drug release
kinetics are controlled by polymer degradation and diffusion.

Liposomes - a spherical vehicle having at least one lipid

bilayer. The liposome can be used as a vehicle for
administration of nutrients and drugs.
+ The parenteral drug manufacturing (Drug Product
Manufacturing) process includes compounding, mixing, filtration,
filling, terminal sterilization, lyophilization, closing, and sealing,
sorting, and inspection, labeling, and final packaging for
distribution.
+ The manufacturing process is complicated, requiring organization
and control to ensure the product meets the quality and the
specifications.
+ Aseptic processing requirement adds more complication but
assures that all dosage forms manufactured are free from any
contamination of microbial, endotoxin, and visible particulate
matter.
+ The manufacturing process initiates with the procurement of
approved raw materials (drug, excipients, vehicles, etc.) and
primary packaging materials (containers, closures, etc.) and ends
with the sterile product sealed in its dispensing package.
+ Sediaan volume kecil disebut juga
dengan Small Volume Parenteral (SVP).
+ Menurut USP, larutan parenteral volume kecil
(SVP) adalah injeksi yang menurut label pada
kemasan, bervolume 100 mL atau kurang

+ Termasuk ke dalam kategori SVP adalah kemasan

injeksi dalam ampul, vial, alat suntik, cartridges,
botol, atau kemasan lain dengan kapasitas
volume 100 mL atau kurang.

+ Sediaan oftalmik yang dikemas dengan

pengemas plastik mudah ditekan termasuk
kategori SVP, jika ukuran kemasan 100 mL atau
kurang
+ SVP meliputi semua tipe produk parenteral, untuk
aplikasi topikal oftalmik, atau injeksi menurut
berbagai rute:
– Rute primer: i.m., i.v., s.c.
– Rute skunder: hiperdermoklisis, intraperitonial,
intraarterial, intraartikular, intrakardiak, intrasisternal,
intradermal, intralesional, intraokular, intrapleural,
intratekal, intrauterin, intraventrikular

+ Formulasi sediaan SVP relatif sederhana: berbahan

aktif, eksipien yang digunakan untuk berbagai
tujuan, sistem pelarut (lebih disukai air), kemasan,
dan penutup kemasan yang sesuai. Atau
diformulasikan dalam bentuk emulsi steril
+ Sterilitas
+ Bebas partikel partikulat
+ Stabilitas fisika dan kimia
+ Isotonisitas
SVP harus isotonis dengan darah, air mata, dan
cairan biologi dalam otot, jaringan, dan cairan
spinal, di mana produk disuntikkan
bermacam bahan digunakan untuk mengatur
tonisitas SVP. Bahan yang biasa digunakan adalah
elektrolit, seperti NaCl dan garam Natrium lain
+ Yang termasuk dalam injeksi terapeutik adalah injeksi antiinfeksi, steroid,
hormon, vitamin, agen kardiovaskular, barbiturat, agen CNS, protein, dan
bermacam-macam obat lainnya.

+ Injeksi biasanya berupa larutan yang mengandung bahan aktif dan bahan
tambahan.

+ Bentuk lain injeksi: larutan hanya mengandung obat, atau obat

disuspensikan dalam medium yang sesuai, atau diformulasikan dalam
bentuk emulsi steril, injeksi yang siap guna (misal: Na-amobarbital untuk
injeksi) atau memerlukan rekonstitusi dari padat menjadi larutan atau
suspensi sebelum digunakan (contoh: amoksisilin untuk injeksi berbentuk
suspensi)
+ Injeksi dapat juga tersedia dalam bentuk
cairan pekat yang harus diencerkan sebelum
digunakan (misal KCl untuk injeksi konsentrat)

+ Injeksi dosis ganda harus mengandung

pengawet antimikroba; umumnya volume
injeksi tidak melebihi 30 mL
+ Produk oftalmik berbentuk obat dalam larutan, suspensi, gel, atau
salep, yang diberikan secara topikal pada permukaan kornea mata.

+ Termasuk produk oftalmik adalah larutan pencuci dalam ukuran

SVP.

+ Sediaan oftalmik harus steril. Sediaan larutan dan suspensi oftalmik

dikemas dalam kemasan polietilen berbobot jenis rendah yang
mudah dipencet untuk memudahkan penggunaan.

+ Salep mata harus steril, bebas dari partikel logam, dan dikemas
dalam tube. Sediaan oftalmik yang berdosis ganda harus
ditambahkan pengawet antimikroba.
+ Ada bermacam agen diagnostik SVP, seperti larutan
yang mengandung iodium radioaktif, kromium,
tekhnesium, besi, dan elemen radioaktif lainnya.

+ Produk ini terutama digunakan untuk evaluasi

fungsi organ.

+ Kebanyakan produk digunakan dalam waktu singkat

(beberapa jam) sesudah dibuat karena waktu
paruhnya sangat singkat.
+ Ekstrak elergenik adalah konsentrat steril
(larutan atau suspensi) dari zat (alergen) yang
bertanggung jawab terhadap sensitivitas pada
manusia, dapat digunakan untuk tujuan
terapeutik atau diagnostik.
+ Ekstrak berbentuk cair (cairan garam fisiologis
sebagai pengencer) atau gliserin (50% gliserin
sebagai pengencer).
+ SVP juga tersedia dalam bentuk serbuk steril,
yang penggunaannya harus direkonstitusi dengan
aqua pro injenctio (USP)

+ Serbuk steril SVP dibuat menurut 2 cara: kering-

beku (freeze-drying) dan pengisian zat padat
(serbuk) pro injectio ke dalam vial/ampul

+ Kebanyakan serbuk kering steril SVP dibuat

dengan cara kering-beku, sering dinyatakan
sebagai liofilisasi.
+ Untuk mendapatkan formula sediaan parenteral
yang baik harus mempunyai data preformulasi
yang meliputi sifat kimia, sifat fisika, dan sifat
biologis, sehingga didapatkan:
– Pembawa yang tepat, yaitu pembawa larut air,
pembawa yang tak larut air atau pelarut campur
– Zat penambah yang diperlukan, meliputi zat
antimikroba (pengawet), komplekson, zat pengisotoni,
antioksidan, dapar, dsb
– Wadah dan jenis wadah yang sesuai
+ Sediaan yang isotonis tidak selalu dapat dicapai
mengingat kadang-kadang diperlukan zat khasiat
dengan dosis tinggi untuk mendapatkan efek
farmakologis yang diinginkan, sehingga isotonis
terlampaui (larutan sedikit hipertonis)

+ Untuk sediaan parenteral subkutan, intradermal,

intramuskular harus dibuat seisotonis mungkin,
sedangkan larutan hipotonis tidak boleh dipakai
+ Setiap larutan sediaan parenteral harus diisikan dalam
jumlah berlebih untuk menjamin jumlah pemberian
cairan secara lengkap.

+ Kehilangan disebabkan oleh pengeluaran gelembung

udara pada saat pemberian dan antisipasi tertinggalnya
cairan dalam wadah yang digunakan selama proses
pembuatan

+ Kelebihan volume dalam kemasan sediaan parenteral

memungkinkan pengguna (dokter, perawat)
menggunakan volume sesuai kebutuhan (jadi tidak
kurang)
+ Kelebihan volume yang direkomendasikan
untuk SVP:

Ukuran isi (mL) Cairan encer (mL) Cairan kental (mL)

0,5 0,10 0,12
1,0 0,10 0,15
2,0 0,15 0,25
5,0 0,30 0,50
10,0 0,50 0,70
20,0 0,60 0,90
30,0 0,80 1,20
50,0 atau lebih 2% 3%
+ Parameter yang dievaluasi untuk sediaan parenteral, meliputi:
– potensi/kadar,
– pH,
– warna,
– kekeruhan,
– bau,
– benda asing,
– toksisitas,
– wadah,
– pengawet
+ Evaluasi dilakukan dengan bantuan alat,
seperti HPLC, spektrometri massa,
spektrofotometer sinar X, sinar UV, sinar
tampak, inframerah, dll.
+ Dosis yang ada tidak boleh kurang dari 90%
dari yang tertera dalam label
+ Perubahan pH dalam sediaan parenteral dapat
menjadi indikasi bahwa telah terjadi
penguraian obat atau telah terjadi interaksi
antara obat dengan wadah (gelas, plastik, atau
tutup karet)
+ Perubahan warna umumnya terjadi pada
sediaan parenteral yang disimpan pada suhu
tinggi (lebih dari 40⁰C), karena suhu tinggi
dapat mempercepat terjadinya penguraian

+ Pencegahan umumnya dengan menghilangkan

oksigen di atas permukaan larutan atau
penambahan komplekson
+ Alat yang dipakai adalah Tyndall, karena
larutan dapat menyerap atau memantulkan
sinar
+ Idealnya larutan parenteral dapat melewatkan
92 – 97% pada waktu dibuat dan tidak turun
menjadi 70% setelah 3 – 5 tahun.
+ Ada penyebab terjadinya kekeruhan sediaan
parenteral, yaitu: benda asing, terjadinya
endapan, dan pertumbuhan mikroorganisme
+ Bau
Pemeriksaan kemungkinan terjadinya bau
harus dilakukan secara periodik, terutama
larutan yang mengandung sulfur atau
antioksidan

+ Benda asing
Sediaan parenteral tidak boleh mengandung
benda asing dengan diameter lebih dari 10µm
+ Toksisitas
Lakukan uji LD50 atau LD0 pada sediaan parenteral selama
penyimpanan

+ Wadah
Evaluasi wadah (gelas, plastik, atau tutup karet) dilakukan
secara periodik untuk mengetahui pengaruhnya terhadap
zat aktif

+ Pengawet
Pada sediaan yang disimpan pada 5C dan 25C dievaluasi
efektivitas pengawet apakah masih efektif atau sudah
berkurang
38
Factors affecting parenteral formulations
+ Physicochemical properties of the drug.
– Unstable in moisture
 Dry
 Suspension
 Replace water by other solvent

– Insoluble in water
 Non-aqueous solvent
 Derivative (salt)
+ Route of drug administration
– IV Aqueous
– Others may not aqueous
+ Desired onset of drug action
– Physical state of the drug (suspension)
– Vehicle (aqueous or not)
+ Duration Oleogenous > suspension > aqueous

39
 Considerations in parenteral preparation
+ Solvents & vehicles must meet special purity & other standard to
assure safety.
+ Added substances (buffer, stabilizers preservatives) should be
approved for parenteral products.
+ Prepared in controlled areas under strict sanitation standards &
personnel specially trained, clothed to maintain sanitation.
+ Packing hermetically sealed container of specific & high purity.
+ Volume slightly excess of the labelled size to help administration.
+ Volume is limited depending on route and type (single or multiple).
+ Dry parenteral should reconstitute fast with ease (Lyophilized).
+ The finished product must meet sterility standard.
+ Must be pyrogen free.
+ No particulate mater

40
 Considerations in parenteral preparation: Vehicles
+ Solvents & vehicles must meet special purity & other standard to assure
sterility, stability and safety.
+ Vehicle used should be:
 pharmacologically inert,
 non toxic and compatible with blood,
 maintain solubility of the, drug,
 be physically and chemically stable
 does not affect the pH.
 Must be pyrogen free.
 No particulate mater.
 The finished product must meet sterility standard.
 Water is the ideal vehicle for most injections since aqueous preparations are
well tolerated by the body.
 Easy visual inspection for particulate contamination, chemical precipitation
and colour change.
 It may accelerate drug hydrolysis resulting in an inert or toxic products..

41
Considerations in parenteral preparation
Solvents / vehicles for injection
+ Can be Water, Water-miscible co-solvents or
Non-aqueous solvents
+ Aqueous is preferred
+ Non-aqueous may be used due
– Drug of limited water solubility
– Drug susceptible to hydrolysis
– Desired physicochemical factors (extended
release)

42
Considerations in parenteral preparation
Solvents / vehicles for injection

+ Suitable vehicle properties

– No irritation, sensitization, toxicity or
pharmacological activity
– Should not affect the activity of the drug
– Should have suitable physicochemical properties
for intended use (stability, viscosity, fluidity with
temperature, boiling point, miscible with body
fluid, low vapor pressure).
– Purity (ease of purification & standardized).
– Must remain clear at 10oC

43
Considerations in parenteral preparation
ADDITIVES / EXCIPIENTS
+ They are substances that are incorporated into the
parenteral dosage form to maintain stability, ensure sterility,
minimize pain & tissue irritation and aid in parenteral
administration.
+ (1) Antimicrobial preservatives
+ (2) Anti-oxidants
+ (3) Buffer
+ (4) Chelating Agents / Sequestering Agents
+ (5) cryoprotectants & lyoprotectants
+ (6)Inert Gas
+ (7) Solubilizing Agents and Surfactants
+ (8) Tonicity modifiers
+ (9) Viscosity modifiers
44
 Considerations in parenteral preparation
ADDITIVES- preservatives
(Antibacterial S & ANTI OXIDANTS)
• Usually added in multiple dose vials to protect the product from
contamination due to repeated dose withdrawal.
• Also added to most unit-dose parenterals which are not terminally sterilized.
• Types of preservatives
• Acidic: Phenols and parabens (Butyl-P-hydroxybenzoate, Methyl-P-
hydroxybenzoate).
• Neutral: Alcohols eg Benzyl alcohol
• Mercurial: Thimerosal
• Quaternary ammonium compounds: benzalkonium chloride.
• ANTIOXIDANTS:
• prevent oxidation of drug during sterilization.
• Mechanism of action
• Preferentially oxidized: Ascorbic acid & Na bisulfite, metabisulfite or sulfite.
• Blocking an oxidation chain reaction: Ascorbic acid, BHT & Tocopherols.
• Complexing agent with catalyst: EDTA
• Synergistic action: acids (citric, phosphoric, tartaric, ascorbic).
45
 Considerations in parenteral preparation
ADDITIVES- Buffers
• Added to maintain pH for Solubility, Stability and Pain reduction

pH Buffer system Conc. (%)

3.5 - 5.7 Acetic Acid/Acetate 1-2

2.5 - 6.0 Citric Acid/Citrate 1-5

6.0 – 8.2 Phosphoric Acid/Phosphate 0.8 - 2

8.2 – 10.2 Glutamic Acid/Glutamate 1 – 2

> 8.0 Carbonic Acid/Carbonate >1

Other systems used in parenterals: Glycine (pH 6.5-7.5), Lactate

(pH 3-6), Maleate (pH 2.5-5.0), Tartarate (pH 3-5)
46