FORMULASI-TEKNOLOGI SED.

STERIL(1)

MATERI KULIAH
I.PENDAHULUAN/INTRODUCTION
* Definisi, contoh sediaan, keuntungan dan kerugian,
II. MACAM SEDIAAN STERIL
* Klasifikasi, contoh, syarat sediaan
III.RUTE PENGGUNAAN
IV. BAHAN PEMBAWA
* Macam
*Syarat
*Purifikasi Air ,( Metoda )
V.PENGEMAS,
*Fungsi,syarat, macam, pencucian dan sterilisasi
VI. STERILISASI
Metoda,
VII. FORMULASI SEDIAAN STERIL
* Preformulasi
* Metode manufacture
VIII.KONTROL KUALITAS,
* Fisika, Kimia dan Biologi

I. PENDAHULUAN
1.Definisi/Istilah-istilah
Contoh Sediaan
2.Keuntungan
3.Kerugian

FIGURE 3.3 Injectable products packaged in multipledose (vial) and single-dose (ampul) containers.

Keberhasilan penyampaian obat/pengobatan dari system infus dapat dapat

diperoleh dengan bantuan Pompa/pum dalam berbagai jenis.

View of a Typical
cGMP Corridor

1.DEFINISI/ISTILAH-ISTILAH
DRUG/OBAT
A drug is defined as an agent intended for use in
the diagnosis,mitigation,treatment,cure, or
prevention of disease in humans or in other
animals

What is a medicine?
Drug as the active ingredient +
excipients formulated into a
suitable dosage form with
complete packaging
Pharmaceutical Dosage Form
( Sediaan Obat )
1.Sterile ( Sterile Dosage Form )
2.Non-sterile ( Non-Sterile Dosage Form )

Definition of sterile dosage forms:

A product introduced in a manner that
circumvents the bodys most protective
barriers,the skin and mucous
membranes, and, therefore, must be
essentially free of biological
contamination
Sediaan Steril ..... Injeksi = Parenteral

* ISTILAH-ISTILAH :

- STERIL
-

STERILISASI
ANTISEPTIK
DESINFEKTAN
- INJEKSI
- INFUS
- DLL

Beberapa Contoh Sediaan Parenteral

FIGURE.Disposable sterile cartridges compatible

with the Carpuject holder. (Courtesy of Hospira, Inc.).

Gb.Sediaan Serbuk Kering Steril

Gb.Monovial
Safety Guard System

FIGURE . Inject-Ease automatically inserts the needle

of an insulin syringe into the skin when activated. (Courtesy
of William B. French, PhD.)

2-3.KEUNTUNGAN DAN KERUGIAN BSS

2. KEUNTUNGAN :
*
*
*
*

AKSI CEPAT
SELURUH DOSIS
MENGHINDARI GIT
KONDISI PASIEN

3. KERUGIAN :
* SAKIT
* ALAT KHUSUS DAN KONDISI
* TENAGA AHLI
* RISIKO PEMBERIAN : - SALAH Obat
-- Dosis

Rapid action/onset
a.Berdasarkan Rute Injeksi

b.BERDASAR BENTUK SEDIAAN

II.MACAM SEDIAAN STERIL

A.KLASIFIKASI ( Bentuk Fisik )

1. Padat
: a. Steril ( serbuk kering
steril,implant)
b. Non Steril
2. Semi Padat :
a. Steril
b. Non Steril
3. Cair( larutan , emulsi , suspensi ) :
a. Steril
b. Non Steril
Rute penggunaan : a. Steril :
parenteral , topikal
b. Non Steril :
a.l.oral , topikal

Parenteral use according to the physical statets of the product(USP):

1.Solution or emulsion of medicaments suitable for injection
2.Dry solids or liquid concentrates containing no additives which, upon
the addition of suitables solvents, yield solutions conforming in all
respect to requirements for injections
3.Preparation the same as described in class 2 but containing one or
more additional substances
4.Suspensions of solids in suitable medium which are not to be injected
intavenously or into the spinal column
5.Dry solids which ,upon the addition of suitable vehicles, become
sterile suspensions
*(1.A suitable Vehicle , 2.Additive , 3.Container/Packaging ).

 Gambar: Sediaan Steril bentuk serbuk

kering steril(Sks = serbuk kering steril)

Tabel1.Obat2 Parenteral yg.Tersedia dlm.btk.SERBUK KERING

STERIL
Nama OBAT

Conc.+Recons.

Stabilitas

ACTION/USE

AcetazolamideSodium

0,5 g Vial+
SWFI
( VIAL = V )
( AMPUL= AP )

2 wks RT,4 wks

Rfrigeration/RF

A.Inhibits
carbonic
anhydrase
enzym
U.To treat
glaucoma,
epilep,dll
A.Interfere with
nucleic acid
metabol
U.To treat
Ewings
Sarcome

Adriamycin HCl

Allopurinol Na

V( 10 mg+ 50
mg lactose),
lyoph
Red powder +2
ml
SWFI

24 hrs RT, 96
hrs
RF

7 dys RF

V,500 mg+10ml
SWFI
Amobarbital Na
Nmt 30 min
AP,

A xanthine
oxidase
Inhibitor
U.To inhibit

Sterile products that are not

parenteral or injectable products
include the following:
1.Topical ophthalmic medications
2.Topical wound healing medications
3.Solutions for irrigation
4.Sterile devices (e.g., syringes,
administration sets, and
implantable
systems)

 TABLE 15.8 EXAMPLES OF IRRIGATION SOLUTIONS

SOLUTION
DESCRIPTION
Acetic acid irrigation, USP
0.25% solution applied topically to bladder for irrigation; pH 2.83.4, calculated

osmolarity 42 mOsm/L; during urologic procedures, washes away blood, surgical

debris

while maintaining suitable conditions for tissue and permitting unobstructed

view
Neomycin and Polymyxin B
sulfates solution for irrigation, USP

Sterile urogenital solution contains 57 mg neomycin sulfate (40 mg neomycin) and

polymyxin B sulfate 200000 U/mL; topical antibacterial in continuous irrigation of

bladder; pH 4.56; 1 mL added to 1 L 0.9% NaCl, administered via three-way catheter

at 1 L/24 h (40 mL/h approx.)

Ringers irrigation, USP
purifi ed water, in

NaCl 8.6 g/L, potassium chloride 0.3 g/L, calcium chloride 0.33 g/L in
same proportions as in Ringers injection. Sterile and pyrogen free; used topically to
irrigate; must be labeled NOT FOR INJECTION; pH 57.5, calculated osmolarity
309 mOsm/L

Sodium chloride irrigation,USP

NaCl in water for injection; 77, 154 mEq/L of each sodium, chloride in 0.45% and
0.9%

solutions, respectively; NaCl irrigation pH 5.3 approx.; 0.45%, 0.9% solutions

calculated osmolarity 154, 308 mOsm/L, respectively. Employed topically to wash

wounds and body cavities where absorption into blood not likely; also employed as

enema; for simple evacuation, 150 mL; for colonic fl ush, 1500 mL may be used
Sterile water for irrigation, USP

Sterilized and suitably packaged. Label designations FOR IRRIGATION ONLY, NOT

FOR INJECTION must appear prominently. Must not contain any antimicrobial or

other added agent

PENGEMAS SEDIAAN STERIL

Gambar: vial-( Single dose dan

Multiple dose )

 TABLE CONSTITUTION OF OFFICIAL

GLASS TYPES
TYPE
GENERAL
DESCRIPTION
I
Highly resistant
borosilicate glass
II
Treated soda lime glass
III
Soda lime glass
NP
General purpose soda
lime glass

 Gb.Sterile filling of vial

Gb.Vial for sterile product made of

Glass type I

 Gb.Ampoule before filling and sealing

 Gb.Ampule sealing

 Gambar : ampul Single dose

 A.Gb.multiple-dose vial of suspension and dry powder

B.Vial for solution including one with light-protective glass
C.Unit dose,disposable syringe D.various ampules

According to the USP monographs :

About 22% are solid preparations that require
solution constitution prior to use.
About 9% are diluent preparations, both small
and large volume.
About 10% are radioisotope diagnostic
preparations

These are examples of sterile drugs prepared and

packaged without pharmaceutical additives such
as buffers, preservatives,stabilizers, and tonicity
agents:
Ampicillin sodium
Ceftizoxime sodium
Ceftazidime sodium
Cefuroxime sodium
Kanamycin sulfate
Nafcillin sodium
Penicillin G benzathine
Streptomycin sulfate
Tobramycin sulfate
* Dikemas dalam bentuk serbuk kering steril

Sterile drugs formulated with pharmaceutical

additives and intended to be reconstituted prior
to injection include the following:
Cyclophosphamide
Dactinomycin
Erythromycin lactobionate
Hydrocortisone sodium succinate
Mitomycin
Nafcillin sodium
Penicillin G potassium
Vinblastine sulfate
*Dikemas dalam bentuk Sediaan Serbuk kering
steril

NOMENCLATURE AND DEFINITIONS

There are five general types of parenteral preparations
listed in the USP:
[Drug] Injection: Liquid preparations that are drug
substances or solutions thereof.
[Drug] for Injection: Dry solids that, upon the addition of
suitable vehicles, yield solutions conforming in all
respects to the requirements of injections.
[Drug] Injectable Emulsion: Liquid preparations of drug
substances dissolved or dispersed in a suitable emulsion
medium.
[Drug] Injectable Suspension: Liquid preparations of
solids suspended in a suitable liquid medium.
[Drug] for Injectable Suspension: Dry solids that, upon
the addition of suitable vehicles, yield preparations

 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).

Packaging:-Small Volume
Parenteral(SVP)(<100 ml)
-Large Volume Parenteral(LVP)
(>100 ml)
Penggunaan :1.Single dose 2.Multiple
dose

Some injections usually packaged and administered in small volume

Injection

Physical Form Category and Comments

Botulinum toxin type A

Powder for
injection

For temporary improvnt. in appearance

of mederate to severe glabellar lines,IM

Chlorpromazine HCl

Solution

Antipychotic drug with antiemetic,not

SQ,IM slowly,avoid directly IV.IV for
Tetanus,surgery

Digoxin

Solution

Cardiotonic,(IM not preferred), IV

Phytonadione

Dispersion

Vit K,Aqueous dispers.,viscous liq.

Procaine penicillin G

Suspension

Anti-infective;IM

Morphine sulfate

Solution

Opioid analgesic,IM ,IV , PCA

Phenytoin sodium

Solution

Anticonvulsant;( IM erratic); slowly IV

Cimetidine HCl

Solution

Histamin H2 antagonist;IM or IV

 Gb.Two 100-ml single-dose plastics

bags for IV-infusion

Table. Some intravenous infusions that may be administered in volume of 1 L or more,

alone or with other drugs
Injection

Usual contents

Category and comments

Amino acid

3.5;5;5.5;7;8.5;10% crystalline
amino acid with or without
varying concentration of electrolyte
or glycerin
2.5;5;10;20 dextrose,other
strengths
Dext.2.5-10%; NaCl 0.11-0.9%
(19-154 mEq sodium)

Fluid or nutrient
replenisher

Dextrose Inj.
Dextrose and Sodium
Chloride Inj.USP
Mannitol Inj.,USP

5,10,15,20,25% mannitol
Ringers Inj.,USP
147 mEq Na,4 mEq K, 4.5 mEq
Lactated Ringers Inj,USP Ca,156 mEq Cl/L
2.7 mEq Ca, 4 mEq K,130 mEq
Sodium Chloride Inj,USP Na,28 mEq lactate/L
0.9% NaCl

Fluid and nutrient

replenisher
Fluid,nutrient,electrolyte
replenisher
Diagnostic aid in renal
function,diuretic,fluid
and nutrient replenisher
Fluid and electrolyte
replenisher
Systemic
alkalinizer;Fluid and
electrolyte replenisher
Fluid and electrolyte
replenisher,isotonic vehc.

Gb.Autoclaving of intravenous
electrolyte solution

Examples of drugs lost from aqueous solutions

during infusion through flexible PVC tubing
include the following:
Amiodarone HCl
Chlorpromazine HCl
Diazepam
Lorazepam
Nitroglycerin
Promazine HCl
Promethazine HCl
Thiopental sodium
Thioridazine HCl
Trifl uoperazine HCl
Warfarin sodium

Seven Basic Characteristics of

Sterile Product Dosage Forms :
1.Safety (freedom from adverse toxicological
concerns)
2. Sterility (freedom from microbiological
contamination)
3. Nonpyrogenic (freedom from pyrogenic
endotoxincontamination)
4. Particle-free (freedom from visible particle
contamination)
5. Stability (chemical, physical, microbiological)
6. Compatibility (formulation, package, other

III.RUTE PENGGUNAAN
1.General/Umum ;
* i.v. ; i.m.; s.c; i.c
2.Khusus a.l :
* intr.card
* intraarticular, intraarterial
* intraperitoneal,intrapleural
*intraventricular,intrathecal, dll

PARENTERAL ROUTES OF ADMINISTRATION

Drugs may be injected into almost any organ or
area of the body, including the
joints(intraarticular),
joint fluid area (intrasynovial), spinal column
(intraspinal), spinal fluid (intrathecal), arteries
(intra-arterial), and in an emergency, even the
heart (intracardiac). However, most injections go
into a vein (intravenous, IV), into a muscle
(intramuscular, IM), into the skin (intradermal,
ID; intracutaneous), or under the
skin(subcutaneous, SC; sub-Q, SQ;
hypodermic,hypo) (Fig. 15.1).

Table 1. Range of dosage forms available for different

administration routes
Adminis
tration
route

Dosage Form

Oral

Solutions, syrups, elixirs, suspenions,emulsions,

gels,powders, granules,capsules,tablets

Rectal

Suppositories, ointments, creams,powders, solutions

Topical

Ointments, creams,
pastes,lotions,gels,solutions,topical aerosol

Parenter Injections( solution, suspension, emulsion forms),

al
steril ( implants,irrigation and dialysis solutions
Lungs

Aerosols(solution,suspension,emulsion,powder
forms),inhalations,sprays,gases

Nasal

Eye

Solutions,inhalations
Solutions, ointments

Ear

Solutions,suspensions,oinments

Tabel 2. Variation in time of onset of action for

different dosage form
Time of onset
of action

Dosage form

Seconds

I.V.-injection

Minutes

I.M and S.C. injections, buccal tablets,

aerosols, gases

Minutes to
hours

Short term depot injections,solutions,

suspensions,powders,granules,
Capsules, tablets, sustained release tablets.

Several hours

Enteric coated formulations

Days

Depot injections, Implants

Varies

Topical preparations

53

Macam Rute Parenteral

5
5

Rute : Intracisternal
- Untuk menarik cairan cerebrospinal
- Pemberian antibiotik [ meningitis ]
- Prosedur
: sulit, tekanan injeksi harus
hati-hati
- Preparation : complete aseptis, pH, density,
free from
particles

5
4

Rute:
intrathecal
PD = peridural
IT =
Intrathecal

5
6

a. Jarum suntik umum [ Ukuran besar kecil ditentukan

nomor ]
Eropa = 1, 2, 14, 16, 18, 20
Jepang ( ASIA )= 18G, 19G, 20G, 21G, 22G, 23G, 24G, 24G,
25G,
26G, 27G (Makin besar nomor semakin
suit)
TERUMO (Jepang), berdinding sangat tipis : NEOLUS

b. Jarum suntik gigi

Terumo (Jepang) ada 3 macam: 25G, 27G, 30G
c. Jarum suntik spinal (Spinal needle)= Lumbal Punchie [ LP ]
Terumo (Jepang): LP ( 18G, -19G_20G_21G_22G_23G25G,
panjang 2,25 3,5)

Gb.Testing Compatibilityof Rubber

Closures with
a solution

 Gambar : sediaan steril bentuk emulsi(

Small Volume)

 Gambar :Sediaan bentuk serbuk kering steril

dengan vehicle untuk dibuat sediaan suspensi

FIGURE . Carpuject, a prefilled unit dose injection

system that includes a reusable, clear, plastic full-length
holder. (Courtesy Abbott Hospital products division.)

IV. FAKTOR-FAKTOR FARMASETIK YANG

BERPENGARUH PADA PENGGUNAAN
PARENTERAL
Kelarutan Obat dan Volume injeksi
Karakteristik Bahan Pembawa
pH dan Osmolalitas Larutan Injeksi
Tipe Bentuk Sediaan
Larutan dalam WFI suspensi
dalam minyak
Bahan Baku Formulasi

Formulasi

( lanjutan)

Beberapa pertimbangan dlm

formulasi :

1.Rute penggunaan
2.Volume injeksi
3.Bhn pembawa( lautan/suspensi )
4.Tekanan osmose lrtan
5.Preservative
6.pH larutan
7.Stabilitas obat & metoda Sterilisasi
8.Specific gravity d larutan
9.Sifat2 suspnsi injk.
10. Sifat2 emulsi injk
11.Pengemas
12.Partkel/Kontmn,
13.Biofarms inj

Osmolarity ---- Tonicity

Osmolarity
( mOsmol / liter )
> 350

Tonicity

Hypertonic

329 350

Slightly hypertonic

270 328

Isotonic

250 - 269

Slghtly hypotonic

0 - 249

Hypotonic

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

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

Prepare 1000 ml of potassium chloride solution containing 80 mEq each of potassium

and chloride ions. The molecular weight of potassium chloride isnn74.6
80 mEq per liter = ( mg per liter ) x 1/74.6
mEq per liter = 5968 mg or 5.968 g
Moles and Millimoles
Konsentrasi dapat dinyatakan dengan moles( M ).
A mole of any substance is the gram-atomic or gram-molecular weight.
*KCl has a gram molecular weight of 74.5 since K=BA 39 and Cl 35.5.
*Oleh karena itu, 1 M KCl = 74.5 g of the salt.
*A 1 M( or molar) solution of KCl contains 74.5 g in 1 L of final solution.
*A millimole (mM ) = 1/1000 a mole
*Berat suatu Zat(kimia) dapat dirubah ke millimol dengan membagi Berat benda dalam
milligram dengan Berat molekul.
Contoh : 1 g KCl = 13.4 mM ( 1000 mg : 74.6 = 13.4 )
Seperti mg/100 ml, istilah millimol adalah suatu indikasi berat bukan dissosiasi
ionik

* 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.
*One Osmol contains the 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.
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

The solutions and suspensions of drugs intended for

injection are prepared in the same general manner as
solutions and disperse systems , with the following
differences:
1. Solvents or vehicles must meet special purity and other
standards ensuring their safety by injection.
2. The use of added substances, such as buffers,
stabilizers, and antimicrobial preservatives, fall under
specific guidelines of use and are restricted in certain
parenteral products. The use of coloring agents is strictly
prohibited.
3. Parenteral products are always sterilized, meet sterility
standards, and must be pyrogen limited.
4. Parenteral solutions must meet compendial standards
for particulate matter.
5. Parenteral products must be prepared in
environmentally controlled areas, under strict sanitation
standards, and by personnel specially trained and clothed
to maintain the sanitation standards

 6. Parenteral products are packaged in special

hermetic containers of specifi c and high quality.
Special quality control procedures are used to ensure
hermetic seal and sterile condition.
7. Each container of an injection is filled to a volume
in slight excess of the labeled volume to be
withdrawn. This overfi lling permits ease of
withdrawal and administration of the labeled volumes.
8. The volume of injection permitted in multiple-dose
containers is restricted, as are the types of containers
(single-dose or multiple-dose) that may be used for
certain injections.
9. Specific labeling regulations apply to injections.
10. Sterile powders intended for solution or
suspension immediately prior to injection are
frequently packaged as lyophilized or freezedried
powders to permit ease of solution or suspension
upon the addition of the solvent or vehicle

Keseragaman Volume
VOLUME TAMBAHANAN

1
6

VI.KECEPATAN PELEPASAN OBAT dari BENTUK

SEDIAAN

AQUEOUS SOLUTION
AQUEOUS SUSPENSION
OLEAGINOUS SOLUTION
OIL-in-WATER EMULSION
WATER-in-OIL EMULSION
OLEAGINOUS SUSPENSION

Fastest realease

Slowest
realease

4
8

MEKANISME PELEPASAN OBAT

1. Aqueous Suspension
Dissolve

DRUG
DRUG
Solid
fine
particles

Diffusion

DRUG
Dissolve in
Absorbed
tissue fluids Partition
ing

2. Oleaginous Solution
DRUGPartition
DRUG
ing Dissolve in
Dissolve
in oil

Diffusion

DRUG

PartitionAbsorbed
tissue fluids
ing

3. OIL-in-WATER EMULSION
Dif. Mix.

DRUGPartition
DRUG
Dillution
DRUG
ing Dissolve DRUG
Dissolve

In oil phase

in aqueous
phase

Diff.
Dissolve in
Partition
Absorbed
tissue fluids ing

4
9

Syarat Suspensi
1. Homogen
2.Mudah disusp. Kembali
3.Mudah dituang ( Pourable = oral )
4.Syringeability dan Injectablity
( Parenteral)
(syringeability.test:a 25-gauge needle, =0,3 mm)
5.Ukuran partikel( kecil/lembut )
6.Kecepatan pengenapan lambat

4. WATER-in-OIL EMULSION
Diffusion

DRUGPartition

DRUG
DRUG
Partition
Into
tissue
Partit.
DRUG fluids
Dissolve
ing Dissolve
ing
Dissolve
Absorbed
in aqueous
In oil phase
in tissue fluids
phase
5. Oleaginous Suspension
DRUG
Suspended in
oil
Dissolution
in tissue fluids

Dissoluti
DRUG on

DRUG

Dissolve In oil
Partit. in
tissue fluids

Dissolve in tissue
fluids

DRUG

Absorbed

5
0

PENGOLAHAN AIR

BAHAN PEMBAWA atau PELARUT

( VEHICLES )

1.Syarat
2.Macam jenis
3.Air
Vehicle ideal :
a.Sumber
b.Syarat WFI
c.Purifikasi air
d.Hasil purifikasi air

Ad.1.. Syarat BAHAN PEMBAWA [VEHICLE] /

PELARUT :
Mudah tersedia, harga terjangkau
Inert (Farmakologi)
Campur dengan cairan badan
Tidak toksik
Non-sensitizing
Tidak mengiritasi
Effective
Stabil
Cair / Menjadi cair pada temperature badan
Tidak dipengaruhi pH
Dapat disterilkan

AIR merupakan solvent yang ideal

Ad.2..Macam/Jenis Pembawa-Pelarut
a. H2O (Water)
- Purified water ( PW )
-Water for Injection ( WFI )
- Sterile Water For Injection ( SWFI )
- Bacteriostatic Water For Injection ( BWFI )
- Water For Irrigation ( WFIr)
b. Pelarut campur air (Water Miscible Solvent)
- Alkohol
-Gliserin
-Propilen glikol
-Polietilen glikol ( PEG cair/BM rendah )
c. Pelarut tak campur air (Water Immiscible
Solvent
- minyak ( a.l. Cotton seed oil, Sesami oil )

2.3. AIR
a. Syarat
- Fisika , Kimia , Biologi
b. Sumber
- air permukaan, air tanah , deep well
c. Pemurnian: - I.E (ion Exchange)
- EDI ( Electrodeionisasi )
- Distilasi
- R.O (Reverse Osmosis)
d. Air Hasil Pemurnian
-PW
-WFI
-SWFI
-BWFI
-WFIr

Pharmaceutical Grade
Water Requirements
Purified Water

Highly Purified Water

(Eur. Pharm. +
USP)

(European
Pharmacopeia)

1.3 S/ cm

1.3 S/ cm

Heavy Metals

0.1 ppm

0.1 ppm

Nitrate

0.2 ppm

0.1 ppm

< 500 ppb

< 500 ppb

< 500 ppb

Microbial Limit

< 100 cfu/ ml

< 10 cfu/ ml

< 10 cfu/ ml

Endotoxines

< 0.25 Eu/ ml

< 0.25 Eu/ ml

Conductivity at 25C

Total Organic
Compound

Water For Injection

(Eur. Pharm.)

USP

1.3 S/ cm

Converting Percent (%) to:

Part Per Million (ppm)
-2

-6

ppm = % x 10

10

% x 10

ppm= % x 10000
Example:
Convert 0,5 % chlorine solution to ppm
chlorine
ppm = % x 10000= 0,5 x 10000
= 5000
ppm
= 5000

AIR
Air untuk Injeksi, Syarat
1.
2.
3.
4.
5.
6.
7.

Jernih
Tidak berwarna
Tidak berbau
pH: 5,0-7,0
Bebas mikroba
Bebas pirogen
Bebas partikel

Batasan terhadap jumlah:

a. Klorida
e. CO2
b. Kalsium
f. Logam berat
c. Sulfat ion
g. Oxidizable Substance
d. Ammonia
h. Total zat padat terlarut
( 10 ppm)

Pemurnian Air
1. Berdasarkan Sumber atau asal :
a. Air permukaan
b. Air tanah

2. Syarat air untuk injeksi (USP, FI):

a. Fisika
b. KImia
c. Biologis

Syarat-syarat tersebut meliputi (USP):

pH (5-7), Khlorida (0,5 ppm), sulfat (1 ppm),

ammonia (0,1 ppm), Calcium (1 ppm), Carbone
dioxide (5 ppm), Logam berat (0,1 ppm sebagai
Cu), zat yang dapat mengoksidasi (lolos uji
permanganate USP), zat padat total (10 ppm),
pyrogen (EU/ml by LAL) 0,25; bebas mikroba.

3. Proses pemurnian air

Pemurnian Air

a. Metode pemurnian:
1)Ion Exchange
Single bed
Mixed bed
Tahap pertukaran ion
Tahap regenerasi (HCl/NaOH)
* ELECTRO DEIONISATION

2)Distilasi
Simple still distilation
Multiple effect still distilation
Kelebihannya dengan simple still dist

3)Reverse Osmosis (RO)

Proses pemurniannjya
Kelebihan dan kekurangannya

Bagan Pengolahan
Air

PROSES PEMBUATAN WFI

Pretreatment untuk WFI

1.Klorinasi [menghambat pertumbuhan
kuman]
2.Prefiltrasi [depth filters: e.g. sand] (-) Iron,
suspended
matter, Silt.
3.Floculasi [e.g: alum]
Removal of
susp. Material
4.Pelunakan air [Ion exchange]
(+) ionion alkali tanah,
Ca, Mg
5.Penyesuain pH [6,0-6,5]
Scale
deposits
6.Deionisasi [ion exchange resion]
pembersihan
sempurna ion-ion
7.Karbon aktif [(-) klorine dan senyawa
organik)

2
4

Alur Pembuatan Aqua proinjeksi

Storage tank
Water Softener

Demineralisator

Raw Water
Finn Aqua
Storage tank

-Air tanah
[ Ca dan Mg ]
+
+
-Air dengan+kesadahan
tinggi [DH= Degree or
+
Hardness sekitar 13-18 DH]
-Water Softener
dilengkapi kolom
+
+
+
resin
(untuk
mengikat Ca dan
+
+
Mg ) dengan melepas H
1-10 DH
-Resin yang jenuh dibersihkan
-kation E
HCl 30%
-anion E
NaOH 30%
-Dimineralisator

KE
AE

-Finn Aqua: 4 kolom destilasi

Tetradest

Water System Schematic

Multimedia Depth Filtration

Multimedia Depth Filter

Source:

Dual Activated Carbon

Filters

Dilute
Concentrates
C

Concentrates
C

Na+
(+)

Cl
Cl

Anodyte

Na+
Cl

Na+

Feed (NaCl)
A. Anion exchange membrane
B. Cation exchange membrane

(-)

Cathodyte

I.DISTILLASI
Steam

Condensor
Boiler
Cold water
Feed water
Receiver

33

TEMPERATURE / ENERGY DIAGRAM for

WATER
o
C
150

Boiling water

Vapou
r

100

50

0
100 kcal

640 kcal

MULTIPLE-EFFECT
EVAPORATOR
Vapo
r
st

Vapo
r

nd

rd

Effec
t
Input
energ
y

Vapo
r

Effec
t
Feed
water

Feed
water

Feed
water

Effec
t

Condense
r

DISTILLATE

Four-Effect Distill
- 0,8 kg air dingin
konden. 1 kg.
distilat
- 0,1 kilo watt/kg energi listrik diperlukan
Perbandingan [still tunggal] :
- 12 kg air dingin, dan
- 1,2 kilo watt/kg energi listrik
Distillasi:
1.Semakin bersih air yang dipakai ( feed
water)
jarang membersihkan
(efficiency)
2.Feed water
diolah sebaik mungkin
3.Peralatan modern
menggunakan PW
Catatan: -Destilasi harus dioperasikan dengan
kecepatan rendah
-Pyrogen (heat stable)
hati-hati

Pemurnian Air

b. Air hasil pemurnian

1. Purified Water
2. Water for Injection (WFI)
3. Sterile Water for Injection
(SWFI)
4. Bacteriostatic Water for
Injection (BWFI)
5. Water for Irrigation (WFIR)

Proses Klorinasi:
1.Membunuh kuman
2.Menghilangkan bau
Senyawa Chlor :
1.Gas chlorin
2.Senyawa hipoklorit
3.Chlorine dioksida
4.Bromine chlorida
5.Chloramine
Obyek : - limbah industri Biasanya negara- kolam renang
negara berkembang,
- air minum
karena
1. Relatif murah
2. Mudah
3. Efektif sebagai
desinfektan

Reaksi chlorinasi (denngan gas chlor /

kaporit)
+
2

Cl
+ 2H O
+ H 2+ 2Cl

+
+

HOCl -

Ca(OCl) + 2H O
2 HOCl
+ Ca membunuh
+ (OH) kuman (desinfektan)
Yang

FIGURE 2 Water plant with holding

tank.

Single bed IE

NaCl

NaCl
CaSO 4

CaSO 4

KE
-SO H
3

HCl

AE

AE

KE

-N-OH

-N-OH

-SO H
3

H2O

NaOH Ca(OH)2

H2O

3
0

NaCl
CaSO 4
AE

Mixture
of
KE+AE
H2O
Mixed bed IE

A.Deionizing stage
B.Regeneration of
the resins

Pharmaceutical Separate Bed Deionizer

Ion Exchange Technology Map

ION-EXCHANGER SYSTEM
GAMBAR
Cara Kerja Ion-Exchanger
Air baku ( Raw water) yang dihasilkan masih mengandung
pengotor mekanik, colloidal polutan, bau, dan warna dari mineral
mangan, besi dll. Karena itu perlu dilakukan proses pendahuluan
dengan Sand filter untuk menyaring pengotoran mekanik, alum
untuk menghilangkan colloidal polutan serta carbo filter untuk
menghilangkan warna dari air, water softener untuk
menghilangkan kesadahan air (Ca++, Mn++ dan Fe++)

Selanjutnya air tersebut dialirkan melalui cation exchanger yang

berisi resin penukar ion positif dimana ion positif yang ada di air
diikat dan diganti dengan ion hidrogen (H+)

Air yang keluar dari cation exchanger selanjutnya

dialirkan melalui anion exchanger yang berisi resin
penukar ion negatif dimana ion negatif yang ada dia
air diikat dan diganti dengan ion hidrogen oksida (OH-)
Dengan demikian air yang keluar Ion Exchanger sudah
tidak lagi mengandung ion positif serta ion negatif dari
mineral yang terkandung di air. Karena itu air yang
dihasilkan disebut air bebas mineral /aqua
demineralisata.
KELEMAHAN:
1. Tidak dapat mencapai persyaratan conductivity <
1S/cm karena daya ikat resin terhadap ion (+) dan (-)
terbatas dan cepat menjadi jenuh.
2. Tidak dapat mencapai persyaratan micro-account <
100 cfu karena proses penukar ion bukan merupakan
proses sterilisasi
3. Tidak dapat mencapai persyaratn TOC
(total Organic
2
Compound) karena kandungan gas CO dalam air
masih tinggi dan tidak direduksi melalui proses penukar

EDI / ELECTRO DEIONIZATION

Merupakan perkembangan dari Ion Exchange System
dimana sebagai pengikat ion (-) dan (+) dipakai juga
elektroda disamping resin. Elektroda ini dihubungkan
dengan arus listrik searah sehingga proses pemurnian
air dapat berlangsung terus menerus tanpa
regenerasi.

Dilute
Concentrate
s
C
A

Concentrate
s
C
A

Na+
(+)

Cl
Cl

Anodyte

(-)

Na+
Cl

Na+

Feed (NaCl)
A. Anion exchange membrane
B. Cation exchange membrane

Cathodyt
e

II. REVERSE OSMOSIS [R.O]

Metode :
1. Air minum
Air laut
2. Limbah [ Cair ]
3. WFI [ USP ]
Pressure

More
concent
sol.

Less
concent
sol.
Water flow

Reverse Osmosis/Continuous
Deionization (RO/CEDI) Process

OSMOSIS :
1. Air
Membran semipermeabel
2. Konsentrasi rendah
Konsentrasi
tinggi
REVERSE OSMOSIS
:
Konsentrasi tinggi
Konsentrasi rendah
Pemisahan Solute [ Charged
ions,
neutral
organics ]
melalui membran semipermeabel, dari
konsentrasi pekat
menuju konsentrasi encer
Organik
Ions

Penyaringan
Fenomena Antarmuka

Presure

ion
feed

Semi permeable
membrane
permeable

Concentrate

[R.O]

Filtrasi (Seri)
Porositas semakin kecil

Partikel kasar
Bakteri
Virus
Pyrogen
Ions

Reverse Osmosis

3
6

Produksi:
1.Air minum [ air laut ]
2.WFI [ USP ]
OSMOSIS: Air
Membran
Semipermeabel
Konsentrasi rendah
P
luar tinggi
kons.
Reverse Osmosis: [ konst. tinggi
konst. rendah ]
Porositas
semakin kecil
RO
Filtrasi
(seri)
Partikel kasar
Bakteri

Virus

pyrogen

ions

3
7

Reverse Osmosis
- Membran [ tepat ]
- Monovalen ion
ion valensi tinggi
- Air [ Feed water ]

Permiat murni
Lebih sulit dari pada

Disesuaikan pH
Dilunakkan
Mekanisme
Partikel bermuatan dipisah /
ditolak
Tegangan antar muka
antara membran air
[ Zat organik BM tinggi
Disaring ]
Mikroba mengumpul pada membran
[ Chlorine dijaga tinggi
]
2
[ Chlorine, Ammonia, CO
Lapisan karbon
aktif

Keuntungan RO:
1.Energi efisien
2.Air hasil relatif banyak
3.Reduksi biaya energi
Pertimbangan
4.Biaya kontrol kualitas
o
5.Segera dipakai [ Temp. 70-80 C ]

Pharmaceutical Reverse Osmosis Unit

RO System Technology Map

Keuntungan RO:
1.Energi efisien
2.Air hasil relatif banyak
3.Reduksi biaya energi
Pertimbangan
4.Biaya kontrol kualitas
o
5.Segera dipakai [ Temp. 70-80 C ]

27

MACAM-MACAM AIR [Perbandingan]

WATER STORAGE SYSTEM

Point of Use

Stea
m
Condensor

WFI
Steril
Return
circuit
Heat
exchange
r
Steam or
hot water

Storage
tank 80

Pum
p

Storage and Distribution

FIGURE 3 WFI
storage tank and
control panels.

Multiple Effect Distribution Technology Map

Vapor Compression Distribution Technology

Map

DAFTAR PUSTAKA
I.Aulton,M.E.,1994, Pharmaceutics,The Science of Dosage Form Design,ELBS,Edinbugh
II.Ansel,H.C,Allen,L.V, and Popovich NG,2011, Pharmaceutical Dosage Forms and Drug Delivery Systems ,
7th ed.,Lippincott, Williams and Wilkins, Baltimore,MD, 1999
III.Avis,K.E.Lachman.L,Lieberman,H.A;,1990, Pharmaceutical Dosage Forms,Parenteral
Medication,vol.1,2,3, Marcel Dekker,NY
IV.Banker,G.S., Rhodes, C.T.,2004, Modern Pharmaceutics,4rd.ed., Marcel Dekker, NY
V.Groves,M.J.,1989, Parenteral Technology Manual, An introduction to Formulation,Production and
Quality aspect of Parenteral Products, sec.Expd.ed, Interpharm PressInc.,IL, USA
VI.Remingtons Pharmaceutical Sciences,2000, 20 th.ed.., Lippincott, Williams and Wilkins, Baltimore, MD,
VII.Turco,S.,,1994, Sterile Dosage Forms, 4 th ed.,Lea & Febiger, Philadelphia.
VIII.Groves,M.J,Olson,W.P. and Anisfeld,M.H.1991, Sterile Pharmaceutical Manufacturing,Applications for
the 1990s,Vol.Interpharm Press,IL,USA
IX. I.Aulton,M.E.,2007, Pharmaceutics,The Design and Manufacture of Medicines,Third Ed.,ELBS,Edinbugh
X.Olson,W.P.and Groves,M.J(eds).,1987,Aseptic Pharmaceutical Manufacturing,Technology For The
1990s,Interpharm Press.
XI.Dll.

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