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Stabilitas bahan obat Overview

In this chapter we will: Identify those classes of drugs that are particularly susceptible to chemical

breakdown and examine some of the precautions that can be taken to minimise the loss of activity

Look at how reactions can be classified into various orders, and how we can calculate the rate constant for a reaction under a given set of environmental conditions

Look at some of the factors that influence drug stability Examine methods for accelerating drug breakdown using elevated temperatures

and see how to estimate drug stability at the required storage conditions from these measurements.

Key point

Drugs may break down in solution and also in the solid state (for example, in tablet orpowder form).

It is often possible to predict which drugs are likely to decompose by looking for specific chemical groups in their structures.

The most common causes of decomposition are hydrolysis and oxidation, but loss of therapeutic activity can also result from isomerisation, photochemical decomposition and polymerisation of drugs.

It is possible to minimize breakdown by optimising the formulation and storing under carefully controlled conditions.

The chemical breakdown of drugsThe main ways in which drugs break down are as follows:

Hydrolysis Drugs containing ester, amide, lactam, imide or carbamate groups are susceptible to

hydrolysis. Hydrolysis can be catalysed by hydrogen ions (specific acid catalysis) or hydroxyl ions

(specific base catalysis). Solutions can be stabilised by formulating at the pH of maximum stability or, in some

cases, by altering the dielectric constant by the addition of non-aqueous solvents.

Oxidation Oxidation involves the removal of an electropositive atom, radical or electron, or the

addition of an electronegative atom or radical.

Oxidative degradation can occur by autooxidation, in which reaction is uncatalysed and proceeds quite slowly under the influence of molecular oxygen, or may involve chain processes consisting of three concurrent reactions: initiation, propagation and termination.

Examples of drugs that are susceptible to oxidation include steroids and sterols, polyunsaturated fatty acids, phenothiazines, and drugs such as simvastatin and polyene

antibiotics that contain conjugated double bonds. Various precautions should be taken during manufacture and storage to minimise

oxidation: The oxygen in pharmaceutical containers should be replaced with nitrogen or carbon

dioxide. Contact of the drug with heavy-metal ions such as iron, cobalt or nickel, which catalyse

oxidation, should be avoided. Storage should be at reduced temperatures. Antioxidants should be included in the formulation.

Isomerisation Isomerisation is the process of conversion of a drug into its optical or geometric isomers,

which are often of lower therapeutic activity. Examples of drugs that undergo isomerisation include adrenaline (epinephrine:

racemisation in acidic solution), tetracyclines (epimerisation in acid solution), cephalosporins (base-catalysed isomerisation) and vitamin A (cis–trans isomerisation).

Photochemical decomposition Examples of drugs that degrade when exposed to light include phenothiazines,

hydrocortisone, prednisolone, riboflavin, ascorbic acid and folic acid. Photodecomposition may occur not only during storage, but also during use of the

product. For example, sunlight is able to penetrate the skin to a depth sufficient to cause photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug.

Pharmaceutical products can be adequately protected from photo-induced decomposition by the use of colouredglass containers (amber glass excludes light of wavelength < 470 nm) and storage in the dark. Coating tablets with a polymer fi lm containing ultraviolet absorbers has been suggested as an additional method for protection from light.

/p1. Hidrolisa

1.1. Furosemide

= 4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid

1.2. Nicotinamide

= niacinamide = nicotinic acid amide = Vitamin PP = 3-pyridinecarboxamide

1.3. Procainamide= 4-amino-N-(2-diethylaminoethyl) benzamide

Gugus laktam:

Core structure of penicillins (top) and cephalosporins (bottom). β-lactam ring in red.

Benzylpenicillin (penicillin G)= (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-

carboxylic acid

Amoxicillin = (2S,5R,6R)- 6-{[(2R)-2-amino- 2-(4-hydroxyphenyl)- acetyl]amino}- 3,3-dimethyl- 7-oxo- 4-thia- 1-azabicyclo[3.2.0]heptane- 2-carboxylic acid

Cephalosporin C= (6R,7R)-3-[(Acetyloxy)methyl]-7-{[(5R)-5-amino-5-carboxypentanoyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Cefoxitin = (6S,7R)-4-(carbamoyloxymethyl)-7-methoxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Clavulanic acid = (2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid

Gugus Imide:

Cycloheximide = 4-[(2R)-2-[(1S,3S,5S)-3,5-Dimethyl-2-oxocyclohexyl]-2-hydroxyethyl]piperidine-2,6-dione

Cycloheximide is an inhibitor of protein biosynthesis in eukaryotic organisms, produced by the bacterium Streptomyces griseus. Cycloheximide exerts its effect by interfering with the translocation step in protein synthesis (movement of two tRNA molecules and mRNA in relation to the ribosome) thus blocking translational elongation. Cycloheximide is widely used in biomedical research to inhibit protein synthesis in eukaryotic cells studied in vitro (i.e. outside of organisms). It is inexpensive and works rapidly. Its effects are rapidly reversed by simply removing it from the culture medium.

Thalidomide = (RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione

Thalidomide is a sedative drug introduced in the late 1950s that was used to treat morning sickness and to aid sleep.[2] It was sold from 1957 until 1961, when it was withdrawn after being found to be a teratogen - a cause of birth defects.[3] Modern uses of thalidomide (trademarked as Thalomid, according to FDA Orange Book) include treating multiple myeloma in combination with dexamethasone,[4] and erythema nodosum leprosum, with strict controls on its use to prevent birth defects.[

Captan = (3aR,7aS)-2-[(trichloromethyl)sulfanyl]-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione

Captan is the name of a general use pesticide (GUP) that belongs to the phthalimide class of fungicides. Though it can be applied on its own, Captan is often added as a component of other pesticide mixtures. It is used to control diseases on a number of fruits and vegetables as well as ornamental plants. It also improves the outward appearance of many fruits, making them brighter and healthier-looking. Captan is utilized by both home and agricultural growers and is often applied during apple production. Captan is cited as Group B2, a probable human carcinogen by the EPA. [2]

C12H15NO3 = 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl methylcarbamate

= Carbofuran, Furadan, Curater

Carbofuran is one of the most toxic carbamate pesticides. It is marketed under the trade names Furadan, by FMC Corporation and Curater, among several others. It is used to control insects in a wide variety of field crops, including potatoes, corn and soybeans. It is a systemic insecticide, which means that the plant absorbs it through the roots, and from here the plant distributes it throughout its organs where insecticidal concentrations are attained. Carbofuran also has contact activity against

pests.

Neostigmine = 3-{[(dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium

Neostigmine (Prostigmin, Vagostigmin) is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.

2. Oksidasi

Steroid

Cholesterol = (10R,13R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol

Cholesterol is required to build and maintain membranes; it modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group on cholesterol interacts with the polar head groups of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which reduces membrane fluidity.[9] In this structural role, cholesterol reduces the permeability of the plasma membrane to neutral solutes,[10] protons, (positive hydrogen ions) and sodium ions.[11]

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Cholesterol is essential for the structure and function of invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis. The role of cholesterol in such endocytosis can be investigated by using methyl beta cyclodextrin (MβCD) to remove cholesterol from the plasma membrane. Recently, cholesterol has also been implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane. Lipid raft formation brings receptor proteins in close proximity with high concentrations of second messenger molecules.[12] In many neurons, a myelin sheath, rich in cholesterol, since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.[13]

Within cells, cholesterol is the precursor molecule in several biochemical pathways. In the liver, cholesterol is converted to bile, which is then stored in the gallbladder. Bile contains bile salts, which solubilize fats in the digestive tract and aid in the intestinal absorption of fat molecules as well as the fat-soluble vitamins, A, D, E, and K. Cholesterol is an important precursor molecule for the synthesis of vitamin D and the steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.[2]

Some research indicates cholesterol may act as an antioxidant.[14]

Cholic acid = 3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid

Other names: 3α,7α,12α-trihydroxy-5β-cholanoic acid

Progesterone = Pregn-4-ene-3,20-dione

Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species

3. Isomerisasi

Tetracycline = (4S,6S,12aS)-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide = C22H24N2O8

Testosterone = (8R,9S,10R,13S,14S,17S)- 17-hydroxy-10,13-dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-3-one

Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles,[1]

birds,[2] and other vertebrates. In mammals, testosterone is primarily secreted in the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid.

In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair.[3] In addition, testosterone is essential for health and well-being[4] as well as the prevention of osteoporosis.[5]

On average, in adult human males, the plasma concentration of testosterone is about 7-8 times as great as the concentration of adult human females' plasma,[6] but as the metabolic consumption of testosterone in males is greater, the daily production is about 20 times greater in men.[7][8] Females also are more sensitive to the hormone.

Estradiol = (17β)-estra-1,3,5(10)-triene-3,17-diol

Estradiol medication

Estrogen is marketed in a number of ways to address issues of hypoestrogenism. Thus, there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C17 (sometimes also at C3) position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cypionate (injectable).

Oral preparations are not necessarily predictably absorbed, and are subject to a first pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, alternative routes of administration that bypass the liver before primary target organs are hit have been developed. Transdermal and transvaginal routes are not subject to the initial liver passage.

Ethinylestradiol, the most common estrogen ingredient in combined oral contraceptive pills, is a more profound alteration of the estradiol structure.

Ethinylestradiol= 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol

Sterol :

β-Sitosterol = 17-(5-Ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol

Other names: 22,23-Dihydrostigmasterol, Stigmast-5-en-3-ol, β-Sitosterin

Alone and in combination with similar phytosterols, β-sitosterol reduces blood levels of cholesterol, and is sometimes used in treating

hypercholesterolemia.[medical citation needed] β-Sitosterol inhibits cholesterol absorption in the intestine.[2] When the sterol is absorbed in the intestine, it is transported by lipoproteins and incorporated into the cellular membrane.[3] Phytosterols and phytostanols both inhibit the uptake of dietary and biliary cholesterol, decreasing the levels of LDL and serum total cholesterol. Because the structure of β-sitosterol is very similar to that of cholesterol, β-sitosterol takes the place of dietary and biliary cholesterol in micelles produced in the intestinal lumen.[4] This causes less cholesterol absorption in the body.

Stigmastanol = (3β)-Stigmastan-3-ol; (3β,5α)-Stigmastan-3-ol; β-Sitostanol; Dihydrositosterin; Dihydrositosterol; Dihydro-β-sitosterol; Fucostanol; Spinastanol; 24α-Ethylcholestanol

Stigmastanol (sitostanol) is a phytosterol found in a variety of plant sources. Similar to sterol esters and stanol esters, stigmasterol inhibits the absorption of cholesterol from the diet.[

Polyunsaturated fatty acids

Omega-3

Omega-3 fatty acids, polyunsaturated

α-Linoleic acid (ALA) =cis, cis-9,12-Octadecadienoic acid= C18H32O2

N−3 fatty acids that are important in human physiology are α-linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid (20:5, n−3; EPA), and docosahexaenoic acid (22:6, n−3; DHA). These three polyunsaturates have either 3, 5, or 6 double bonds in a carbon chain of 18, 20, or 22 carbon atoms, respectively. As with most naturally-produced fatty acids, all double bonds are in the cis-configuration, in other words, the two hydrogen atoms are on the same side of the double bond; and the double bonds are methylene interrupted, i.e., there are two single bonds between each pair of adjacent double bonds.

Chemical structure of alpha-linolenic acid (ALA), an essential n−3 fatty acid, (18:3Δ9c,12c,15c, which means a chain of 18 carbons with 3 double bonds on carbons numbered 9, 12, and 15). Although chemists count from the carbonyl carbon (blue numbering), physiologists count from the n (ω) carbon (red numbering). Note that, from the n end (diagram right), the first double bond appears as the third carbon-carbon bond (line segment), hence the name "n−3". This is explained by the fact that the n end is almost never changed during physiologic transformations in the human body, as it is more energy-stable, and other carbohydrates compounds can be synthesized from the other carbonyl end, for example in glycerides, or from double bonds in the middle of the chain.

Chemical structure of eicosapentaenoic acid (EPA).

Chemical structure of docosahexaenoic acid (DHA).

Omega-6

Omega-6 fatty acids, polyunsaturated

γ-Linolenic acid (GLA) = all-cis-6,9,12-octadecatrienoic acid= C18H30O2

Omega-9

Omega-9 fatty acids, mono- and polyunsaturated

Oleic acid = (9Z)-Octadec-9-enoic acid= C18H34O2

Phenothiazine= thiodiphenylamine, dibenzothiazine, dibenzoparathiazine, 10H-dibenzo-[b,e]-1,4-thiazine, PTZ= C12H9NS

Turunannya:

Chlorpromazine = 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine= C17H19Cl N 2S

Chlorpromazine works on a variety of receptors in the central nervous system, producing anticholinergic, antidopaminergic, antihistaminic, and weak antiadrenergic effects. Both the clinical indications and side effect profile of CPZ are determined by this broad action: its anticholinergic properties cause constipation, sedation, and hypotension, and help relieve nausea. It also has anxiolytic (anxiety-relieving) properties. Its antidopaminergic properties can cause extrapyramidal symptoms such as akathisia (restlessness, aka the 'Thorazine shuffle' where the patient walks almost constantly, despite having nowhere to go due to mandatory confinement, and takes small, shuffling steps) and dystonia. It is known to cause tardive dyskinesia, which can be irreversible.[2] In recent years, chlorpromazine has been largely superseded by the newer atypical antipsychotics, which are usually better tolerated, and its use is now restricted to fewer indications. In acute settings, it is often administered as a syrup, which has a faster onset of action than tablets, and can also be given by intramuscular injection. IV administration is very irritating and is not advised; its use is limited to severe hiccups, surgery, and tetanus.[3]

Perphenazine = 2-[4-[3-(2-chloro-10H-phenothiazin-10-yl) propyl]piperazin-1-yl]ethanol= C21H26Cl N 3O S  

Perphenazine is used to treat psychosis (e.g. in schizophrenics) and the manic phases of bipolar disorder. Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms,[4] but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics.[5]

In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows.[citation needed] Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients.

Perphenazine has been used in low doses as a 'normal' or 'minor' tranquilizer in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.[6]

[citation needed]

Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients and, in high doses (up to 100 mg per day), for patients with life-threatening (febrile) catatonia, a state in which the patients are extremely agitated, but unable to express themselves. In this situation perphenazine may be used together with electroconvulsive therapy and correction of electrolytes and fluids in the body.

A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the life of the unborn. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose.

Simvastatin= (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-

hexahydronaphthalen-1-yl 2,2-dimethylbutanoate= C25H38O5

The primary uses of simvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease.[1] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels sufficiently. [1]

Polyene antimycotics, sometimes referred to as polyene antibiotics, are a class of antimicrobial polyene compounds that target fungi.[1] These polyene antimycotics are typically obtained from some species of

Streptomyces bacteria. The polyenes bind to ergosterol in the fungal cell membrane and promote leakiness which may contribute to fungal cell death. Amphotericin B, nystatin, and natamycin are examples of polyene antimycotics. Polyene antimycotics, sometimes referred to as polyene antibiotics, are a class of antimicrobial polyene compounds that target fungi.[1] These polyene antimycotics are typically obtained from some species of Streptomyces bacteria. The polyenes bind to ergosterol in the fungal cell membrane and promote leakiness which may contribute to fungal cell death. Amphotericin B, nystatin, and natamycin are examples of polyene antimycotics.

Amphotericin B

Nystatin

Natamycin

3. Isomerisasi

(R)-(–)-L-Epinephrine or (R)-(–)-L-adrenaline =(R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol= C9H13N O 3

Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding.[12] It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivative, and dextrose, respectively, are currently preferred.[12]

Tetracycline = (4S,6S,12aS)-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide = C22H24N2O8

Vitamin A =(2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol = (Retinol) =C20H30O