INKOMPATIBILITAS OBAT

(DRUG INCOMPATIBILITY)

SuprApt0
suprapto@ums.ac.id
Fakultas Farmasi UMS

*Disampaikan pada kuliah Blok Rational Therapeutics

Fakultas Kedokteran UMS 2017
DEFINITION OF DRUG
INCOMPATIBILITY:

 Drug incompatibility refers to

interactions between two or more
substances which lead to changes in
chemical, physical, therapeutic
properties of the pharmaceutical
dosage form.
DEFINITION OF
INCOMPATIBILITIES

 Incompatibility is an undesirable
reaction that occurs between the drug
and the solution, container or another
drug.
 The two types of incompatibilities
associated with intravenous
administration are physical and
chemical.
Referensi: Josephson 2006, RCN 2005, Douglas et al.
2001.
TYPES OF DRUG
INCOMPATIBILITY
 Therapeutic
incompatibility
 Physical
incompatibility
 Chemical
incompatibility
THERAPEUTIC INCOMPATIBILITY
 Definisi:
adalah modifikasi efek terapi
suatu obat terkait oleh pemberian obat
secara bersamaan (kombinasi) atau
lainnya.

 Disebut juga = interaksi obat (drug

interactions)
MECHANISMS OF THERAPEUTIC
INCOMPATIBILITY

Dibagi menjadi dua grup:

1. Pharmacokinetics: absorption,
distribution, metabolism and excretion.
2. Pharmacodynamics: synergism,
antagonism, altered cellular transport, effect
on the receptor site.

(Ini dibahas di kuliah interaksi oleh Dr. Em S.)

PHYSICAL INCOMPATIBILITY
(INCOMPATIBILITAS FISIK)
 Physical incompatibilities sering disebut
dengan incompatibilitas farmasetik
(pharmaceutical incompatibilities).
 Definisi: interaksi antara dua atau lebih
zat yang dapat menyebabkan perubahan
pada warna (color), bau (odor), rasa
(taste), viskositas (viscosity) dan bentuk
(morphology).
MANIFESTATIONS OF PHYSICAL
INCOMPATIBILITY:
Manifestasi incompatibilitas Fisik meliputi:
1. Insolubility of prescribed agent in
vehicle
2. Immiscibility of two or more liquids
3. Liquification of solids mixed in a dry
state (called eutexia)
INSOLUBILITY (TIDAK LARUT)
 The following factors affect the solubility of
prescribed agent in vehicle and may render it
less soluble:
1. Change in pH
2. Milling
3. Surfactant
4. Chemical reaction
5. Complex formation
6. Co-solvent
CONTOH KETIDAKLARUTAN 1
Rx:
Benzalkonium chloride
Sodium lauryl sulfate

 They are not mixed together because

benzalkonium chloride is positive charged
while sodium lauryl sulfate has negative
charge.
 By mixing together a precipitate is formed.
EXAMPLE 2:
Rx:
Ephedrine sulfate
Menthol
Liquid paraffin

 Thisprescription is not prescribed because

ephedrine sulfate is a salt which is soluble in
water but insoluble in organic solvents, oil
and paraffin.
IMMISCIBILITY (TIDAK CAMPUR)
 Immiscibility dari dua atau lebih cairan
(liquids)
 Manifestasi ini adalah nanpak jernih
(clearly) pada sediaan emulsion, creams,
lotions, beberapa tipe salep (ointments).
 Pemisahan dua fase pada sediaan obat
(pharmaceutical dosage forms)
merupakan penanda adanya
immiscibility ini.
 BEBERAPA FAKTOR YANG DAPAT
MENYEBABKAN IMMISCIBILITY:
1. Pencampuran yang belum homogen
(incomplete mixing)
2. Penambahan surfactant dengan:
 Kadar yang tidak sesuai (unsuitable concentration)
 Waktu yang tidak tepat (alse time of addition)
 Ketidakseuaian tipe emulsi (unsuitable for the type of
emulsion)
3. Adanya m.o. (presence of microorganisms)
 Some bacteria grow on constituents of mixture i.e. gelatin,
Arabic gum (PGA), etc.
 Others produce enzymes which oxidize the surfactant
4. Suhu (temperature)
 Storage must be in room temperature to prevent separation
LIQUIFICATION OF SOLIDS MIXED IN A
DRY STATE (EUTEXIA)

 Jika dicampurkan dua zat padat bersamaan,

terjadi perubahan titik leburnya.
 It happens through the following methods:

1. Formation of liquid mixture: when the solid

substance is soluble in another solid substance
which lead to decrease of its melting point and
conversion to a liquid in certain ratios.
2. Exit of crystalline water: by mixing hydrated
crystals and dry crystals, crystalline water
diffuse to dry crystals.
CHEMICAL INCOMPATIBILITY
Def.: Reaction between two or more substances which
lead to change in chemical properties of pharmaceutical
dosage form.
Types of chemical changes:
1. Oxidation

2. Hydrolysis

3. Polymerization

4. Isomerization

5. Decarboxylation

6. Absorption of CO2

7. Combination

8. Formation of insoluble complexes

OXIDATION
 Def.:
Oxidation is defined as loss of electrons
or gain of oxygen (kehilangan é or
penambahan O2)

 Auto-oxidation: It is a reaction with oxygen

of air which occur spontaneously without
other factors.
 Pre-oxidants: are substances catalyze
oxidation process i.e. metals, some impurities.
 FACTORS LEAD TO OXIDATION:
1. Presence of oxygen
2. Light: it can cause photo-chemical reactions: chemical reaction
occur in presence of light
3. Temperature: elevated temperature accelerate oxidation
reaction
4. PH: each drug has its ideal pH for stability. Any change in pH
affect drug stability and may accelerate oxidation reaction
5. Pharmaceutical dosage form: oxidation reaction occur in
solutions faster than in solid dosage forms
6. Presence of pre-oxidants as metals and peroxides
7. Type of solvent used: oxidation reaction occur faster in
aqueous solution than others.
8. Presence of unsaturated bonds: as double and triple bonds
(oils) which undergo easier than saturated bonds (margarine) for
oxidation.
 PROTECTION OF DRUGS FROM OXIDATION:
1. Addition of Antioxidants: Vitamin E, vitamin C and inorganic sulfur
compounds: thiosulfate and polysulfide
2. Addition of chemicals which form complexes with metals i.e. EDTA,
Benzalkonium chloride
3. Protection from light:
a. Using of dark container
b. Storage in dark places
c. Packaging with substances which absorbed light i.e. Oxybenzene
4. Choice of suitable pharmaceutical dosage forms which reduce the
possibility of oxidation process (solid dosage forms are better than solutions)
5. Maintenance of pH by using buffer solution
6. Choice of suitable solvent (rather than water)
7. Storage in low temperature
8. Protection from air by:
a. Using good closed containers
b. Replacement of oxygen by nitrogen
B. REAKSI OKSIDASI REDUKSI

Oksidator
Fe 3+ Hg 2+ Cu 2+ KMnO4 Iodium NaNO2 KNO3

Reduktor
Alkaloid
Vit C Vit E dan Iodida Glyserin tannin fenol
garamnya
FENOMENA CHEMICAL INCOMPATIBILITY
 a. Reaksi asam basa (1)

Zat bereaksi asam Zat bereaksi basa

• Asetosal • Na-Bicarbonat
• Barbital • Ephedrin
• Bismuth sub nitrat • Hexamin
• Vitamin C • Aminophilin
• Codein
 a. Reaksi asam dan basa (2)

1. Codein + NH4Cl Codein HCl + NH3

2. Bismuth Sub salisilat + Na bicarbonat
 a. Reaksi asam dan basa (3)
Bahan Bahan Gas yang timbul
Fe Carb Acid Citric gas CO2

Codein NH4Cl Gas NH3

Codein Ichtyol Gas NH3

Ext gentian, Succus Liq, Liq NaHCO3 gas CO2

Ext
KMnO4 NaHCO3 Gas CO2
 c. Reaksi Presipitasi (pengendapan)
1. CaBr2 dg Na-Salisilat terbentuk Ca-Sal (tdk larut)
2. Na Benzoat dan CaCl2 terbentuk Ca-Benzoat (tdk larut)
3. AgNO3 dan Cocain HCl terbentuk AgCl (tdk larut)
4. CaBr2 dan NaHCO3 terbentuk CaCO3 (tdk larut)
5. Papaverin HCl dan KI terbentuk papaverin hidroiodida (tdk
larut).
 d. Perubahan warna (1)
Fenol, asam
salisilat

Ungu
Preparat
besi
 d. Perubahan warna (2)

• Adrenalin berubah merah

(adrenokrom) oleh adanya senyawa
basa.
• Apomorfin HCl dlm suasana basa
berubah menjadi hijau
• Larutan yg mengandung Na-Sal dan
NaHCO3 akan berwarna tua
 e. Terurai

• Asetosal dalam suasana lembab terurai

menjadi asam asetat dan asam salisilat
• Na-Phenobarbital dalam larutan terurai
menjadi fenil etil asetil ureum
• Na-Barbital dalam larutan terurai menjadi
dietil asetil ureum.
 f. Penggaraman (Salting)
• Merupakan bentuk pengendapan
• Berkurangnya kelarutan zat-zat karena penambahan
garam atau zat lain yang dapat larut ke dalam larutannya,
sehingga zat yang semula larut menjadi tidak lagi larut.
Contoh:
1. Mucilago gom, tragakan, agar-agar dengan Bismut
Subnitrat
2. Garam-garam morfin, efedrin, dan kodein berkurang
kelarutannya dengan adanya NaCl
 Berbagai
Contoh
incompatibilitas
obat
dengan
eksipients
Resiko Incompatilitas bagi Pasien
Resiko Incompatilitas bagi Pasien
Financial impact
Pengatasan Inkompatibilitas
Pengatasan Incompatibilitas
Pengatasan Inkompatibilitas
Pengatasan Inkompatibilitas
 “Ya Allah
sembuhkan
saudara kami
yang sedang
sakit. Aamiin”
Bagaimana,
faham kan?
Ada
pertanyaan?
 Tugas-tugas-tugaS

• Carilah inkompatibiltas fisik dan kimia

pada sediaan serbuk berikut dan
diskusikan cara penanganannya!
• Hasil dikumpulkan di sebagai nilai tugas
Saudara pada Dr. Em Sutrisna, 26 Oct 16!
 Problem 1
R/ Aminophyllin 0,200
Antalgin 0,300
Vit C 0,050
m.f pulv dtd no XII
Da in cap
S.3.d.d cap 1
Pro: Bp. Wahid
 Problem 2

R/ FeSO4 0,050
Bic Natric 0,100
Aspirin 0,300
m.f pulv dtd no XII
S t d d pulv 1
Pro : Anak Leli (12 th)
 Problem 3

R/ Hyoscami pulv 0,015

Norit 0,050
Paracet 0,250
Sach Lact qs
m.f. pulv dtd No XII
S.t.d.d pulv II
Pro: An. Renata (6 th)
 Problem 4
R/ Elaeosacch ment pip 0,090
Hexamin 0,050
Aspirin 0,500
m f cap dtd no XV
S 3 d d cap 1
Pro: Sdr. Ronald
 Tugas 5

• Carilah fenomena inkompatibiltas fisik

dan kimia yang terjadi pada sediaan
lainnya dan diskusikan cara
penanganannya!
 Referensi
• Braun, 2011, Drug incompatibility, Risk prevention in
infusion therapy.
• Sonali S. Bharate, Sandip B. Bharateb and Amrita N.
Bajajc, 2010, Interactions and incompatibilities of
pharmaceutical excipients with active
pharmaceutical ingredients: a comprehensive review.
SELAMAT
BELAJAR
Salam S3:
Semoga Sukses
Selalu