INKOMPATIBILITAS OBAT

(DRUG INCOMPATIBILITY)

SuprApt0
suprapto@ums.ac.id
Fakultas Farmasi UMS

*Disampaikan pada kuliah Blok Rational Therapeutics

Fakultas Kedokteran UMS 2019
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 Prof. 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)
 Thefollowing 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 (API)
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,
sudah faham
kan?
Ada
pertanyaan?
 Tugas-tugas-tugaS

• Carilah satu kasus inkompatibiltas fisik

dan kimia dalam dunia kedokteraran!
• Carilah inkompatibiltas fisik dan kimia
pada sediaan serbuk berikut dan
diskusikan cara penanganannya!
• Hasil dikumpulkan minggu depan sebagai
tugas Saudara pada:
Sabtu, 12 Oktober 2019!
 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