ASEPTIS, terkait dengan sediaan / item Steril

Aseptis, meliputi :
1.proses pembuatan
2.penyediaan sediaan/item
3.pemakaian/penggunaan
 Aseptic Technique and Sterile Product Prepration

1. Aseptic Preparation of Parenteral Product

2. Safe Handling of Cytotoxic and Hazardous Drugs
3.IV-Admixture
 Unidirectional airflow
The operator should
never come between the
air source and the product.

Horizontal airflow
www.ors.od.nih.gov/ds/pubs/bsc/graphics/fig3.gif

Vertical airflow
 ASEPTIC TECHNIQUES
Meliputi :
1.Use of Syringes and Needles
2.Removal of Sterile Syringe from Package and
Placement of Needle
2.Withdrawal of contents of Ampuls
3.Withdrawal of contents from Vials
4. Reconstitution of Sterile solids
5.Procedure for Plate counts
6.Evaluation of Aseptic Filling Technique
7.Suggested Procedural Approach for
Extemponeous Preparations
KEBIJAKAN PENERAPAN CPOB

MENJADI PRIORITAS BAGI YANG MEMPRODUKSI:

PRODUK DENGAN KEKRITISAN TINGGI:
•Narrow therapeutic window
•Toksisitas tinggi
•Sediaan steril
•Produk biologi
•Produk yang dibuat melalui proses yang kompleks
Definition of sterile dosage forms:
A product introduced in a manner that circumvents the
body’s most protective barriers,the skin and mucous
membranes, and, therefore, must be “essentially free”
of biological contamination
 Producing sterile drug products
Terminal sterilization
• Product containers are filled and
sealed under high-quality
environmental conditions
designed to minimize
contamination, but not to
guarantee sterility.
• Product in its final container is
subject to a sterilization process
such as heat or irradiation.
Aseptic processing
• Drug product, container, and
closure are subject to
sterilization separately, and then
brought together.
• Because there is no process to
sterilize the product in its final
container, it is critical that
containers be filled and sealed in
an extremely high –quality
environment.
 A.Aseptic processing
Drug product, container, and closure are subject to
sterilization separately, and then brought together.

Because there is no process to sterilize the product

in its final container, it is critical that containers be
filled and sealed in an extremely high –quality
environment
Aseptic processing
• Drug product, container, and closure are subject to
sterilization separately, and then brought together.
• Because there is no process to sterilize the product in
its final container, it is critical that containers be
filled and sealed in an extremely high –quality
environment
Aseptic technique
this is the preparation of pharmaceutical products
from steril ingredients by procedures that exclude the
access of viable microorganism into the products. It is
used for those products that would be adversely by
being subjected to sterilisation process.
According to the USP, injectable materials are separated into five general
types. These may contain buffers, preservatives, and other added
substances.
1. Injection: Liquid preparations that are drug substances or solutions
thereof (e.g., Insulin Injection, USP).

2. For injection: Dry solids that, upon addition of suitable vehicles, yield
solutions conforming in all respects to the requirements for injections (e.g.,
Cefuroxime for injection, USP).

3. Injectable emulsion: Liquid preparation of drug substance dissolved or

dispersed in a suitable emulsion medium (e.g., Propofol,USP).

4. Injectable suspension: Liquid preparation of solid suspended in a suitable

liquid medium (e.g., Methylprednisolone Acetate Suspension, USP).

5. For injectable suspension: Dry solid that, upon addition of suitable

vehicle, yields preparation conforming in all respects to the requirements for
injectable suspensions (e.g., Imipenem and Cilastatin for injectable
suspension, USP).
 Tabel1.Obat2 Parenteral yg.Tersedia dlm.btk.SERBUK KERING STERIL
Nama OBAT Conc.+Recons. Stabilitas ACTION/USE
Acetazolamide- 0,5 g Vial+ SWFI 2 wks RT,4 wks A.Inhibits carbonic
Sodium ( VIAL = V ) Rfrigeration/RF anhydrase enzym
( AMPUL= AP ) U.To treat glaucoma,
epilep,dll
A.Interfere with nu-
Adriamycin HCl V( 10 mg+ 50 mg 24 hrs RT, 96 hrs cleic acid metabol
lactose), lyoph RF U.To treat Ewing”s
Red powder +2 ml Sarcome
SWFI
A xanthine oxidase
Allopurinol Na V,500 mg+10ml 7 dys RF Inhibitor
SWFI U.To inhibit produc
tion of uric acid

A. As barbiturats
Amobarbital Na AP, 250mg;500mg Nmt 30 min U.Sedativ, hypn.
For injection: Dry solids that, upon addition of suitable vehicles,
yield solutions conforming in all respects to the requirements for
injections (e.g., Cefuroxime for injection, USP).

• Gambar: Sediaan Steril bentuk serbuk kering steril(Sks = serbuk kering steril)

• Rekonstitusi : adalah penambahan pengencer pada suatu konsentrat cairan atau

serbuk dengan tujuan untuk menghasilkan konsentrasi tertentu.
• Gambar : sediaan steril bentuk emulsi( Small
Volume)
• Gambar :Sediaan bentuk serbuk kering steril
dengan vehicle untuk dibuat sediaan suspensi
Rekonstitusi serbuk Injeksi
Obat-obat yang tidak stabil tersedia dalam bentuk
serbuk
Obat-obat ini direkonstitusi menjadi bentuk larutan
atau suspensi sebelum di injeksikan
Definisi: Rekonstitusi adalah penambahan pengencer
pada suatu konsentrat cairan atau serbuk dengan tujuan
untuk menghasilkan konsentrasi tertentu
Pernyataan : Etiket pada kebanyakan serbuk rekonstitusi
biasanya mencantumkan jumlah pengencer yang harus
ditambahkan dalam mililiter untuk mencapai
konsentrasi tertentu, umumnya dinyatakan dalam
miligram per mililiter.
Antibiotik oral suspensi kerings
Gb.Sediaan Serbuk Kering Steril
Pertimbangan Dosis Untuk Obat-obat perenteral
Obat-obat parenteral diberikan dengan injeksi melalui rute
a.l. IV,IM,SC, Intraarteri dan intrathekal.

Obat-obat ini harus memenuhi standar sterilitas dan

osmolaritas yang ketat.

Karena obat-obat ini diinjeksikan langsung ke dalam jaringan

atau aliran darah setiap kesalahan perhitungan dapat
menyebabkan efek samping yang serius....termasuk
perhitungan dalam REKONSTITUSI........
Rekonstitusi : 1. Dosis ( volume yang sesuai )
2. Stabilitas....(unstable drug )
Titik Kunci : Pada saat menyiapkan konsentrasi obat
yang tepat, seorang Apoteker harus berhati-hati
dalam mengikuti petunjuk pada etiket serbuk
rekonstitusi untuk Injkesi. Volume serbuk harus
diperhitungkan jika volume ini menambah volume
total larutan secara bermakna.

Contoh Soal
1.Berapa mililiter air steril untuk Injeksi( SWFI) yang
harus ditambahkan pada vial 2 g
Aztreonam(Azactam) untuk memperoleh
konsentrasi akhir 100 mg/mL.
Karena tidak ada keterangan lain , maka obat
dianggap menempati volume yang dapat diabaikan :
2 g x 1000 mg/1 g x 1 mL/100 mg = 20 mL

2.Seorang dokter menulis resep penisilin G kalium

400.000 unit IM. Dosis harus diberikan dalam
volume 1 mL agar sesedikit mungkin menimbulkan
rasa nyeri pada pasien. Informasi berikut ini
tercantum pada kemasan dalam untuk vial
5.000.000 unit :
“Penyiapan larutan : Tambahkan 18 mL pelarut
untuk mencapai konsentrasi akhir 250.000 U/mL.”
For injection: Dry solids that, upon addition of suitable vehicles,
yield solutions conforming in all respects to the requirements for
injections (e.g., Cefuroxime for injection, USP).

• Gambar: Sediaan Steril bentuk serbuk kering steril(Sks = serbuk kering steril)

• Rekonstitusi : adalah penambahan pengencer pada suatu konsentrat cairan atau

serbuk dengan tujuan untuk menghasilkan konsentrasi tertentu.
Berapa banyak pelarut yang harus ditambahkan ke
dalam vial untuk mendapatkan kekuatan yang
dibutuhkan?
Volume Total = 5.000.000 unit x 1 mL/250.000 unit = 20 mL
Volume yang ditempati serbuk = 20 mL – 18 mL= 2 mL
5.000.000 U x 1 mL/400.000 U= 12,5 mL volume total untuk
menghasilkan konsentrasi yang diinginkan.
12, 5 mL – 2 mL = 10,5 mL air untuk ditambahkan.

3. Seorang Apoteker rumah sakit menerima permintaan sebagai

barikut :
Nafsilin natrium 800 mg dalam 100 mL NS
Apoteker tersebut menggunakan vial Nafsilin 1 g dengan
petunjuk pada etiket sebagai berikut :
 “ Jika direkonstitusi dengan 3,4 mL pelarut, tiap vial
mengandung 4 mL larutan “.
Namun ia merekonstitusi vial tersebut dengan 5 mL
air steril dan bukan dengan dengan air steril 3,4 mL
sebagaimana tercantum dalam etiket. Berapa banyak
dari larutan ini yang harus ditambahkan pada 100 mL
air salin normal untuk mencapai dosis yang
dibutuhkan?
Volume yang ditempati serbuk=4 mL- 3,4 mL=0,6 mL.
Volume total yang salah diencerkan = 5 mL + 0,6 mL=
5,6 mL
800 mg x 1 g/1000 mg x 5,6 mL/ 1 g = 4,48 mL
4. Suatu vial yang mengandung 6 g obat antibiotik
untuk injeksi memiliki petunjuk pada etiket sebagai
barikut :
“Tambahkan 8,6 mL air steril untuk( SWFI ) injeksi
untuk mendapatkan konsentrasi akhir 1g/ 2 mL”
Setelah memeriksa pekerjaan teknisi anda ,
(Apoteker) sadar bahwa ia(teknisi) menambahkan
6,8 mL air steril kedalam vial bukan 8,6 mL
sebagaimana tercantum pada etiket. Berapakah
konsentrasi larutan ( dalam mg/mL) yang dibuat
oleh teknisi tersebut.
Volume Total= 6 g x 2 mL/1 g = 12 mL
Volume serbuk = 12 mL – 8,6 mL = 3,4 mL
Volume Total yang salah diencerkan = 6,8 mL + 3,4
mL = 10,2 mL
Konsentrasi = 6 g/10,2 mL x 1000 mg/1 g= 588,24
mg/mL

5. Petunjuk untuk Injeksi IM sefamandol(Mandol)

adalah sebagai berikut :
“ Rekonstitusi tiap gram sefamandol dengan 3 mL
dari salah satu pelarut berikut: air steril untuk
injeksi, air bakteriostatik untuk injeksi, injeksi NaCl
0,9 % atau injeksi NaCl bakteriostatik.”
Berapakah konsentrasi akhir vial sefamandol 2 g jika
direkonstitusi mengikuti petunjuk tersebut?
Volume pengencer yang akan ditambahkan =
2 g x 3 mL/1 g = 6 mL
Konsentrasi Larutan = 2 g/ 6 mL x 1000 mg/ 1 g =
333,33 mg/mL
STABILITY.....?
 STABILITY
Stability : is the extent to which a product retains, within
specified limits, and throughout its period of storage and use,
the same properties and characteristics that it possessed at the
time of its manufacture.
USP 25/NF 20 , stability :
1.Chemical ,Each active ingredient retains its chemical integrity
and labeled potency, within the specified limits.

2.Physical. The original physical properties, including

appearance, palatability, uniformity, dissolution, and
suspendability, are retained

3.Microbiological, Sterility or resistance to microbial growth is

retained according to the specified requirements. Antimicrobial
agents that are present retain effectiveness within the specified
limits.
4. Therapeutic. The therapeutic effect remains unchanged

5.Toxicological. No significant increase in toxicity occurs.

Instability , describes chemical reactions that are “...

Incessant, irreversible, and result in distinctly different
chemical entities(degradation products), that can be both
therapeutically inactive and possibly exhibit greater toxicity.

Incompatibility generally refers to visually evident and

....physicochemical phenomena such as concentration-
dependent precipitation and acid-base reactions, with the
products of reaction manifested as a change in physical
state, including protonation-deprotonation equilibria
2.Q10 - Metode untuk prediksi Shelf-life
The “Q10” adalah perbandingan dari dua konstante
kecepatan reaksi yang berbeda.
Didefinisikan sebagai berikut :
Q10 = K(T + 10)/KT
KT = konstante kecepatan reaksi pada suhu T , dan
K(T+10) = konstante kecepatan reaksi pada suhu 10ᴼ
lebih tinggi( T+100).
Nilai Q = 2, 3 dan 4 ... Berhubungan dengan nilai Ea yang
berbeda : 2 = 12,2 kcal/mol
3 = 19,4 kcal/mol
4 = 24,5 kcal/mol
Bila nilai Ea tidak diketahui digunakan nilai 3(medium)
Q10 = 3
Persamaan yang sebenarnya yang digunakan untuk
estimasi Shelf-life adalah :
t90(T2) = t90(T1)/Q10 pangkat(∆T/10)
t90(T2) = the estimated shelf-life,( T2 ).
t90(T1) = the shelf-life pada temperatur T1
∆T = perbedaan temperatur T2 dan T1(T2-T1)
Dari persamaan diatas dapat dilihat bahwa kenaikan
nilai positif dari (∆T/10) akan menurunkan Shelf-life
dan penurunan nilai (negatif) dari (∆T/10) akan
menaikkan Shelf-life.
Contoh :
1. Suatu sediaan disimpan pada suhu ruang( 25ᴼ C )
meiliki ED = 1 minggu. Berapa Shelf-life bila disimpan
pada refrigerator( 5ᴼ C ).
t90(T2) = t90(T1)/Q10 pangkat(∆T/10)
= 1/3pangkat(-20/10)
= 1/3pangkat -2 = 9 minggu
2. Suatu sediaan disimpan pada suhu 5ᴼ C dengan Shelf-
life = 9 minggu. Berapa Shelf-life bila disimpan pada
suhu 25ᴼ C.
t90(T2)= t90(T1)/Q10 pangkat (∆T/10)
= 9/3 pangkat(20/10) = 1 minggu
Ea( untuk soal 1 dan 2 ) = 19,4 kcal/mol
Aseptis
Terminally sterilized ( Sterilisasi akhir )
Aseptic Processing :
I.Building and Facilities
II. Personel Training and Qualification
III. Components( Active Ingredients and Excipients)
IV.Containers and Closures
V. Endotoxin Control
VI. Time Limitations
VII. Process Validation and Equipment Qualification
VIII. Process Simulation( Media Fills )
Three main aspects to aseptic process validation and equipment
qualification for aseptic processing :
a. process simulation testing(media fills)
b.filtration efficiency, and
c. Sterilisation of equipment and materials.
View of a Typical
cGMP Corridor
A Weigh Room
FASILITAS
– Desain
– Constraction
– Kualification
– Maintenance
Aseptic manufacturing facility design
• The sterile envelope refers to all the steps carried out during
and following the final sterile filtration step through process
completion, which occurs after filled product containers are
sealed and a risk of environmental
• contamination to the product is eliminated.

These steps include:

• Adjuvant, buffer and media formulation
• Addition of excipients
• Adjustment of concentration to achieve target potency
• Sterile filtration
• Component preparation
• Filling, stoppering/plugging, and sealing of product in final
dosage containers
Parameter Penentuan Klas :
1.Jumlah Partikel di udara lingkungan
2.Jumlah Mikroba di udara lingkungan dan
Permukaan Obyek
3.Jumlah Pergantian Udara ( Air Change )
4.Kecepatan Aliran Udara ( Air Flow ),Pola aliran Udara
5.Filter ( Jenis dan Posisi )
6.Perbedaan Tekanan Antar Ruang
7.Temperatur ( t ) dan Kelembaban Relatif ( RH )
 Ref. PICS GMP 2006 WHO TRS 902

AS PIC FDA At rest In operation

EA s Maximum permitted number of particles/m3 equal to or above
N
0,5 mm 5mm 0,5mm 5mm

I A 100 3 500 0 3 500 0

(UDAF)
I B 100 3 500 0 350 000 2000
(Turb.)
II C 10 000 350 000 2 000 3 500 000 20 000

III D 100 000 3 500 000 20 000 Not Not

defined defined
IV NC NC Not defined Not defined Not Not
defined defined

(LAF/UDAF) = laminar air flow or uni-directional air flow

(Turb.) = turbulent or non-uni-directional air flow
AIR HANDLING UNIT ( AHU )( seperangkat alat ),
Fungsi , mengontrol :
* Suhu, Kelembaban, tekanan udara,
Tingkat kebersihan( jumlah partikel/mikroba)
Pola aliran udara, jumlah pergantian udara,dll
AHU, terdiri dari :
1.Cooling coil ( Evaporator ), untuk kontrol t dan RH
2.Static Pressure Fan ( blower ),menggerakan udara
3.Filter(kendali/kontrol : partikel & mikroba )
a.Prefilter(35%), b.medium filter ( 95% )
c. HEPA-filter ( 99,997% )
4. Ducting,saluran tertutup aliran udara
5.Dumper,pengatur jumlah udara ke ruang produksi
Aseptic Processing: Essential Elements

Facility

Documentation Equipment

Aseptic
Finish Product Processing
Process
Testing

Control &
Personnel
Verification
 The four pillars of a
robust * aseptic process

–Personnel training & monitoring

–Environmental monitoring
–Facilities design & HVAC validation
–Process simulation (media fills)
 Personnel Training & Monitoring
• Avoiding contamination means knowing the
potential sources of contamination
– Personnel
– Equipment
– Air/liquids
– Drug product
– Containers/closures
– Outside environment
Anything Brought in contact with, or in the vicinity of, the
product is a potential source of contamination!
 Personnel: Hygiene

• Avoid cleanrooms when ill

• Frequent bathing and shampooing
• Avoid getting sunburned
• Avoid cosmetics such as face powder, hair sprays,
perfumes and aftershave
• Clothing should be clean, nonfrayed and nonlinting
• Avoid smoking
 If people are a major source of
contamination how do we avoid
contaminating the product
while we process it?

www.cellgenix.com/rundgang/pix/rg_7b.jpg
 PEMBUATAN PRODUK STERIL
• Pakaian dan mutunya disesuaikan dengan kelas
kebersihan area kerja (34)
• Lihat POP CPOB 2006 Lampiran 5.1b
• Pakaian Pelindung Sesuai Dengan Ruang kelas
Kebersihan.
Salah !

Salah !
 VALIDASI SEDIAAN STERIL
Program Validasi Aseptik Sterilisasi Akhir
1. Personalia Tim Validasi Disusun Tim validasi Disusun Tim validasi
2. Fasilitas Ruangan Kelas A,B dan kelas C di Kelas C dan D
Pengolahan & Pengisian bawah LAF. HOOD Unit Pengendalian Udara
Validasi terhadap : Unit
Pengndalian Udara
-Tekanan Udara
-Suhu Udara
-Kelembapan Udara
-Jumlah Partikel
-Jumlah Mikroba
-Pertukaran udara per Jam
Integritas Filter HEPA
3. Fasilitas Penunjang Kualifikasi Fasilitas Penunjang Kualifikasi fasilita Penunjang
4. Peralatan Produksi
- Autoclave Dilakukan Uji Kualifikasi Dilakukan Uji Kualifikasi
- Oven Dilakukan Uji Kualifikasi Dilakukan Uji Kualifikasi
5. validasi proses Media Fill Tidak dilakukan
Pengisian
Horizontal Laminar Air Flow ( LAF )
 Unidirectional airflow
The operator should
never come between the
air source and the product.

Horizontal airflow
www.ors.od.nih.gov/ds/pubs/bsc/graphics/fig3.gif

Vertical airflow
 Ref. PICS GMP 2006 WHO TRS 902

AS PIC FDA At rest In operation

EA s Maximum permitted number of particles/m3 equal to or above
N
0,5 mm 5mm 0,5mm 5mm

I A 100 3 500 0 3 500 0

(UDAF)
I B 100 3 500 0 350 000 2000
(Turb.)
II C 10 000 350 000 2 000 3 500 000 20 000

III D 100 000 3 500 000 20 000 Not Not

defined defined
IV NC NC Not defined Not defined Not Not
defined defined

(LAF/UDAF) = laminar air flow or uni-directional air flow

(Turb.) = turbulent or non-uni-directional air flow
 Facilities: Cleanroom Classification

Class 10,000 cleanroom

Class 100 cleanroom

http://www.americancleanrooms.com/am/photogallery_08.html
Gowning

http://www.coleparmer.com/techinfo/techinfo.asp?htmlfile=CleanroomGarments.htm&ID=63
 Personnel: Behavior
Minimize movement: Work slowly and purposefully
Particles >= 0.3µm emitted per minute !

Personnel Snap Membrane

Activity Smock Coverall

No Movement 100,000 10
Light Movement 500,000 50
Heavy Movement 1,000,000 100
Change Position 2,500,000 250
Slow Walk 5,000,000 500

Note: Light/heavy movement refer to partial body movements (motioning with arm, tapping toes, etc.).
Change of position refers to whole body motion (standing up, sitting down, etc.).

Austin Contamination IndexSource: Encyclopedia of Clean Rooms, Bio-

Cleanrooms and Aseptic Areas, Dr. Philip Austin, PE, 2000
B.Aseptic Technique
Contact sterile materials only with sterile instruments:
– Sterile instruments should be held under Class 100
conditions between uses and placed in sterile
containers
– Operators should not contact sterile products,
containers, closures, or critical surfaces with any part
of their gown or gloves
What’s wrong with this picture?
CORRECT
What’s wrong with this picture?
CORRECT
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 “Sterile drug manufacturers should have a keen
awareness of the public health implications of
distributing a nonsterile product. Poor CGMP conditions
at a manufacturing facility can ultimately pose a life-
threatening health risk to a patient.”

FDA Guidance “Sterile Drug Products

Produced by Aseptic Processing-Current
Good Manufacturing Practice” 2004.
• Asepsis- “ A state of control attained by using an
aseptic work area and performing activities in a
manner that precludes microbiological contamination
of the exposed sterile product”
» Guidance for industry: Sterile Drug Products Produced by Aseptic
Processing-Current Good Manufacturing Practice.
FDA, September 2004
Asepsis is the practice to reduce or eliminate
contaminants (such as bacteria, viruses, fungi,
and parasites) from entering the operative field
in surgery or medicine to prevent infection.
Ideally, a field is "sterile" — free of contaminants
— a situation that is difficult to attain. However,
the goal is elimination of infection, not sterility.
» http://en.wikipedia.org/wiki/Asepsis
 Media fill Protocol
 Key element: acceptance criteria
Filled units per Contaminated units permitted
run (action level)
3000 0
4750 1
6300 2
7750 3 The table indicates the
9150 4 maximum permitted number
of contaminated units per
10510 5
various Media Fill “run sizes”
11840 6 to indicate a 0,10%
13150 7 contamination limit with a
14430 8 95% confidence level
15710 9
16960 10 Health Canada
Premises( Building and Facilities )
Building :
- Storage
- weighing area
- bottle washing
- laundry/changing area
- preparation
- filling area
- sterilisation area
- inspection and labelling
- bonded area and release
 COMPONENT OF an IV-ADMIXTURE PROGRAM
1. Preparation Area
2. Policy and Procedures
3. Stability
4. Incompatibility
5. Aseptic Technique
6. Labeling and Checking Systems
7. Quality Assurance and Control
8. Auxiliary Labels
9. Equipment
QC Micro: LAL Assay
(Limulus amebocyte lysate)

ENDOTOXIN LIMIT FOR WFI IS

0.25EU/ml
Tonicity and Tonicity agent
- For every injectable product to be isotonic with
physiologic fluids
- Not an essential requirement for small-volume
injectable(IV)
- Into the eye or spinal fluid must be isotonic
- S.C tissue and muscles also should be isotonic to
minimize pain and tissue irritation.
- Tonicity adjusting agents :
* electrilyte( NaCl )
* glycerin
* mono – or disaccharides
Tonicity :
- To minimize tissue damage and irritation
- Reduce hemolysis of blood cells
- Prevent electrolyte imbalance upon administration
of small volume parenterals(svp)
Isotonic solutions exert the same osmotic pressure
as blood plasma.
A 1 % NaCl solution has a freezing point of -0,58
(derajat celcius) and is assigned a Sodium Chloride
equivalent, E, of 1,00.
The freezing point of blood(serum) is -0,52der.celc.,
the same as a 0,9 % w/v solution of NaCl.
In the absence of a sodium chloride equivalent the Liso
method can be used as shown by Goyan, et al , in 1944.
The Liso is the value at which a specific compound type
will be isotonic with blood. It is related to sodium
chloride equivalent in the following manner :
E = 17(L iso)/M,
M = BM dari substance.
Contoh :
Make a 2 g/100 mL solution of Sodium cephalotin
isotonic using sodium chloride.
BM Na-cepahalotin = 238, Liso cephal. = 3,4
E = 17 x 3,4/238 = 57,8/238 = 0,24 g – eq
2 gram Na Cephalotin = 2x 0,24 = 0,48 g, maka untuk
isotis perlu penambahan NaCl....
TABLE : Liso Values for Various Types of Additives in Parenteral Formulations

Compound type Liso Example

Nonelectrolyte 1,9 Sucrose

Weakelectrolyte 2,0 Phenobarbital
Divalent electrolyte 2,0 Zinc sulfate
Univalent electrolyte 3,4 Sodium chloride
Unidivalent electrolyte 4,3 Sodium sulfate
Diunivalent electrolyte 4,8 Calcium chloride
Unitrivalent electrolyte 5,2 Sodium phosphate
Triunivalent electrolyte 6,0 Aluminium chloride
 TABLE : Ionization of Common Salts

Salt Cation Anion

NaCl Na+ Cl-

Sodium Chloride Sodium ion Chloride ion
Ammonium NH4+ Cl-
Chloride Ammonium ion Chloride ion
CaCl2 Ca ++ Cl-
Calcium Chloride Calcium ion Chloride ion
Na3C6H5O7 3 Na+ C6H5O7....
Sodium Citrate Three Sodium ions Citrate ion
Electrolytes given parenterally are most often requested
and expressed in milliequivalents(mEq).
Equivalent weight = Atomic weight(g)/Valence
Examples :
Equivalent weight of Sodium = 23g/1 = 23 g
Equiv. Weight of NaCl = 58,8 g/1 = 58,8 g
Equiv. Weight of Calcium = 40 g/2 = 20 g

Milliequivalent weight = Equivalent weight/1000

Examples :
mEq weight of sodium = 23/1000 23 mg = 1 mEq
mEq weight of NaCl = 58,5 g/1000 = 58,5 mg = 1 mEq
mEq weight of calcium = 20 g/1000 = 20 mg = 1 mEq
Milliequivalents =Weight(g)/Milliequivalent weight(g)
Calculation Examples :
How many milliequivalents are there in 5,0 g of
Potassium chloride
Weight(g)/Milliequivalent(g) = 5,0/0,0746 = 67 mEq

To find the weight present in a given number of

milliequivalents of material, the formula is :
Weight(g)= Milliequivalent x Milliequivalent weight(g)
How many grams of Potassium chloride are
represented by 5 mEq ?
5 x 0,0746 = 0,373 g of potassium chloride
Persyaratan of Sterile Product Dosage Forms :
1.Safety (freedom from adverse toxicological concerns)

2. Sterility (freedom from microbiological contamination)

3. Nonpyrogenic (freedom from pyrogenic—endotoxin—

contamination)

4. Particle-free (freedom from visible particle contamination)

5. Stability (chemical, physical, microbiological)

6. Compatibility (formulation, package, other diluents)

7. Tonicity (isotonic with biological fluids)

IV. FAKTOR-FAKTOR FARMASETIK YANG BERPENGARUH PADA
FORMULASI dan PEMBUATAN SEDIAAN PARENTERAL
Kelarutan Obat dan Volume injeksi
Karakteristik Bahan Pembawa
pH dan Osmolalitas Larutan Injeksi
Tipe Bentuk Sediaan
Larutan dalam H2O→ suspensi dalam minyak
Bahan Baku Formulasi

15
 Osmolarity ---- Tonicity

Osmolarity Tonicity
( mOsmol / liter )

> 350 Hypertonic

329 – 350 Slightly hypertonic

270 – 328 Isotonic

250 - 269 Slghtly hypotonic

0 - 249 Hypotonic
* There is a relationship between milliequivalent weight and millimole.
* If the ion has a valence of one, then the milliequivalent weight is equal to the
millimole.
• If the ion has a valence of two , then 1 mM equals 2 mEq.

Osmols and Milliosmols

A semipermeable membrane separates two solutions containing dissolved solids, as is
found in biologic system and body compartments.

*Fluid from one compartment moves across the membrane to the other

*Movement is toward the solution having a larger number of dissolved particles. The
force created by this movement is termed “osmotic pressured”

*In Osmotic relationships the important factor is the total number of particles present,
both the ions and the molecules dissolved in solution.
*The number of dissolved particles can be expressed as
OSMOLS(Osm) or, more commonly , milliosmols( mOsm).

*An Osmol is the weight of a chemical substance dissolved in 1

L of water that exerts an osmotic pressure equal to that exerted
by a gram-molecular weight of an un-ionized substance
dissolved 1 L of water same number of particles as does 1 M.
* Concentrations of nonelectrolytes are usually expressed in
moles.
*The concentration is the same when expressed in osmols.
For Example : 1 M of glucose is the same as 1 Osm of
glucose since it does not ionize.
*For electrolytes the particles formed by ionization must be
considered in osmotic relationship.
One mole NaCl ionizes into 1 M of Na and 1 M of Cl-, thus representing 2 Osm.
- For exmp., 1 L of Dextrose Injection, 5%, contains 280 mOsm.( 50 g dextrose:
BM dextrose, 180, = 0.280 M or 280 mM.
Since dextrose is un-ionized,the millimole concentration is the same as the
milliosmol concntration or 280 mOsm.

- For 1 L of NaCl injection containing 9 g of NaCl , 9: 58.4 =0.154 M or 154 mM

per liter.
Since NaCl ionized into two ions, 154 mM per liter multiplied by two gives the
concentration in milliosmol or 308 mOsm per liter.
OSMOLS and Milliosmols
Exmp. 5% Dextrose Inj.,1000 ml,BM Dextr. 180( 1000 x 5% = 50 g /l )
50/180 = 0.280 M or 280 mM/l
280 mM/l x 1 = 280 mOsm/l
0.9% NaCl Injec.,1000 ml( BM NaCl = 58.4 )( 1000 x 0.9% = 9 g/l)
9/58.4 =0.154 M or 154 mM/l …. 154 mM/l x 2 = 308 mOsm/l
 XII.LARUTAN ISOTONIS
Isotonis : ≈ larutan Na-Chloride 0.9%
Paratonis : a. Hipotonis
b.hipertonis
Tonisitas dipengaruhi oleh jumlah partikel
Rumus untuk menghitung tonisitas,
1.Freezing-point Depression(BP)
W = ( 0.52 – a )/ b
W = weight in grams of adjusting substance in 100 ml of final solution
a= depression of freezing point of water produced by substance in solution,
calculated by multiplying value for 1% sol.by strength of sol.expresd as % w/v
b= depression of freezing point of water produced by 1 % w/v of adjusting
substance
Examples :
1.Prepare 100 ml of a solution of methadone HCl 10 mg. per ml. ( 1
per cent ) and make it isotonic with sodium chloride
a= 0.101 ; b = 0.576
W = 0.52 – (0.101 x 1 )/0.576 W= 0.73 g(gm).

2.Berdasarkan nilai Freezing Point

Examples :Prepare 100 ml of a solution of ascorbic acid isotonic with
blood
Freezing point of blood serum = - 0.52 der.celc.
Freezing point of a 1 % solution of ascorbic acid=- 0.105 der.Celc
Then, 0.105 : 0.52 = 1 : X
0.105x = 0.52
X = 4.95 g ascorbic acid to be used.
3.Factor Dissosiasi
h = Mh/fh {( 0,28- ( fa/Ma x a + fb/Mb x b +....)} g/L
Factor Disosiasi:
Non-Dissosiasi fh = 1, Contoh : glucose, gliserin
As. atau basa lmh fh = 1,5
Asam atau Basa kuat,Garam, fh = 1,8

4.Equivalent NaCl
1 g Zat A ≈ 0.37 g NaCl
100 ml larutan Zat A memerlukan tambahan NaCl = ..... G NaCl
5.Grafik , dll
■ Ocular dosage forms are commonly used to treat local
ocular disorders, e.g. Infection and inflammation;
however, intraocular disorders, notably glaucoma, may
also be successfully treated.
■ Ocular dosage forms are principally solutions,
ointments and suspensions. Intraocular injections are
available for the treatment of more serious disorders.
■ These formulations exhibit similar concerns as
comparator formulations regarding physical and
chemical stability.
■ Ocular dosage forms must be sterile.
■ Nasal and otic dosage forms are non-sterile dosage
forms that are inserted into the nasal cavity and ear
canal (respectively) for the treatment of local disorders.
• Advantages and disadvantages of ocular dosage forms
• Advantages
• ■ The application of the therapeutic agents directly to the site of action ensures
that the therapeutic agent is available at higher concentrations than may be
achieved following oral administration.
• ■ Administration of the therapeutic agent locally ensures that the incidence of
side-effects is minimised.
• ■ Following training, the administration of the dosage form locally to the eye
may be easily performed by the patient.
• Disadvantages
• ■ The retention of the drug at the site of action is relatively poor, due
principally to the low tear volume (7 μl for the blinking eye, 30 μl for the non-
blinking eye). The typical volume of two drops of a solution formulation is circa
100 μl and therefore the majority of the applied dose is lost either through
spillage on to the face or via the lacrimal duct.
• ■ In addition, the retention time of applied solutions on the surface of the eye
is poor. For example, it has been reported that, following the administration of
a pilocarpine solution to the eye, removal of the solution from the precorneal
region ofthe eye occurs in less than 2 minutes, resulting in absorption of
approximately 1% of the originally applied dose of drug.
• Therefore, to overcome these deficiencies in practice, the
patient is required to administer the ocular solution
formulations (containing high concentrations of therapeutic
agent) frequently, which is inconvenient and may lead to
patient non-compliance. These inadequacies have inspired
pharmaceutical scientists to devise strategies by which the
• retention of the drug within the precorneal region may be
enhanced.
• ■ Ocular formulations are sterile and therefore specialist
• facilities are required for the manufacture of these dosage
forms.
• ■ Local side-effects may be experienced to ocular dosage
forms (to either the high concentration of therapeutic agent (
5% w/w) or excipients used in the formulation). Typically pain
and irritation are the major side-effects encountered by
patients.
• ■ The application of ointment formulations to the eye may
result in a temporary blurring of vision.
• Administration of therapeutic agents to the eye
• The main anatomical features of the eye are illustrated in Figure 6.1. The main
features of the eye that are of interest for ocular drug delivery and hence the
formulation of ocular dosage forms are:
• (1) conjunctiva; (2) cornea; and (3) lacrimal fluid.
• Conjunctiva
• ■ The conjunctiva is located at the side of the eye and joins on to the cornea and
eyelids.
• ■ The surface area of the conjunctiva is large (circa 18 cm2).
• ■ The conjunctiva helps produce and maintain the tear film.
• ■ The permeability of the conjunctiva to the diffusion of therapeutic agents is
greater than that of the cornea.
• Cornea
• ■ The cornea is composed of three layers:
• – epithelium (adjacent to the conjunctiva): a multilayered epithelium that is rich
in lipids
• – stroma (central region): this is an aqueous matrix composed of collagen and
keratocytes
• – endothelium: a lipid-rich, single-cellular epithelium that maintains corneal
hydration.
• ■ The diffusion of drugs into the inner chambers of the eye is controlled by the
cornea; diffusion occurs via paracellular routes.
• ■ The lipid outer and inner layers (epithelium/endothelium) of the cornea
and the predominantly aqueous stroma control drug diffusion into the
internal regions of the eye. To be effectively absorbed, therapeutic agents
must exhibit intermediate solubility in both these lipid and aqueous
phases and must be of low molecular weight.
• ■ The cornea is non-vascular and negatively charged.
• Lacrimal fluid
• ■ Lacrimal fluid is secreted from glands and is located on the surface of
the eye.
• ■ The pH of the lacrimal fluid is 7.4 and this fluid possesses a good buffer
capacity (due to the presence of carbonic acid, weak organic acids and
protein), being able to neutralise unbuffered formulations effectively over
a wide range of pH values (3.5–10.0).
• ■ Lacrimal fluid is isotonic with blood. Typically ocular aqueous dosage
forms are not specifically formulated to be isotonic (0.9% w/w NaCl
equivalent) and may be formulated within a range of tonicity values
equivalent to between 0.7 and 1.5% w/w NaCl.
• ■ The rate of turnover of lacrimal fluid is approximately 1 μl/min and the
blinking frequency in humans is circa 15–20 times per minute. These
physiological functions act to remove the therapeutic agent/formulation
from the surface of the eye.
Formulation considerations for aqueous ocular dosage forms
• There are two categories of aqueous ocular dosage forms:
• (1) ocular solutions; and
• (2) ocular suspensions.
• Whilst the vast majority of aqueous ocular dosage forms are solutions,
• suspensions may be required whenever the therapeutic agent exhibits
problems regarding chemical stability or, in the case of steroids (e.g.
dexamethasone, prednisolone), the potency of the lipophilic drugs is
greater than that of the water-soluble salts. The majority of formulations
considerations for ocular dosage forms are similar to those described for
pharmaceutical solutions in general. Accordingly the main considerations
for the formulation of ocular solutions and suspensions are as follows.
• Choice of drug salt for use in ocular solutions
• One of the main determinants surrounding the choice of salt type for
inclusion in solution formulations is the solubility – the salt form being
chosen to achieved the required solubility. To compensate for the poor
retention of therapeutic agents within the precorneal region (and therefore
to achieve the maximum pharmacological effect), the concentration of
therapeutic agents in ocular solutions is relatively high.
• Drug absorption across the cornea
• The successful treatment of glaucoma using ocular formulations
requires that there is sufficient drug absorption across the
cornea.
• To be effectively absorbed the drug must exhibit differential
solubility, i.e. the ionised and non-ionised forms coexist. The
effects of pH and ionisation on the absorption of drugs across
the cornea are represented in Figure 6.2.
• As may be observed, sufficient concentration of the nonionised
form is required to partition into and diffuse across the lipid-rich
outer layer of the cornea (the epithelium). The inner layer of the
cornea (the stroma) is predominantly aqueous and therefore
ionisation of the drug must occur to enable partitioning into this
phase. Following diffusion to the interface of between the
stroma and the endothelial (lipid-rich) layer, absorption of the
• non-ionised (but not the ionised) form occurs. The non-ionised
drug then diffuses to the endothelium/aqueous humour
interface where ionisation and dissolution into the aqueous
humour occur.
 FEATURES AND USE OF OPHTHALMIC OINTMENTS
AND GELS
• Among the dosage forms used in the topical
• treatment of conditions and diseases of the eye
• are ointments and gels. Other ophthalmic dosage
• forms used topically include solutions, suspensions,
• and inserts, discussed elsewhere in
• this text. Systemic therapy also may be undertaken,
• as in the use of diuretics in the adjunctive
• treatment of glaucoma.
TABLE 10.3 EXAMPLES OF OPHTHALMIC OINTMENTS

OINTMENT COMMERCIAL PRODUCT ACTIVE INGREDIENT CATEGORY

Chloramphenicol Chloromycetin 1% Antibacterial

Ophthalmic Ophthalmic antibiotic
Ointment (Parke-Davis)

Dexamethasone Decadron Phosphate 0.05% Anti-infl

sodium Ophthalmic Ointment ammatory
phosphate (Merck) adrenocortical
ophthalmic steroid

Gentamicin sulfate Garamycin Ophthalmic 0.3% Antibacterial

Ophthalmic Ointment (Schering) antibiotic

Isofl urophate Floropryl Sterile 0.025% Cholinesterase

ophthalmic Ophthalmic inhibitor
Ointment (Merck)
Polymyxin B– Per gram: polymyxin Antimicrobial
bacitracin Polysporin Ophthalmic B sulfate, 10,000 U;
ophthalmic Ointment (Pfi zer) bacitracin zinc, 500U