MODULE 2. SOFT AND ASEPTIC nDOSAGE FORMS. PHARMACEUTICAL INCOMPATIBILITIES.
CONTENT MODULE 4. MEDICINAL FORMS THAT REQUIRE ASEPTIC MANUFACTURING nCONDITIONS. PHARMACEUTICAL INCOMPATIBILITIES.
LESSON 26. PHARMACEUTICAL nINCOMPATIBILITIES.
Drug nIncompatibility
Drug nIncompatibility
• Definition of Drug nIncompatibility:
Drug Incompatibility refers to ninteractions between two or more substances which lead to changes in
chemical, physical, therapeutic nproperties of the pharmaceutical dosage form.
• Types of Drug Incompatibility
1. Therapeutic incompatibility
2. Physical incompatibility
3. Chemical incompatibility
1. Therapeutic incompatibility
• Definition of Therapeutic nincompatibility
It is the modification of the ntherapeutic effect of one drug by the prior concomitant administration of
another. (It is also called drug ninteractions)
• nMechanisms of ntherapeutic incompatibility
They are divided into two groups:
1. Pharmacokinetics:
involve the effect of a drug on another nfrom the point of view that includes absorption
,distribution , metabolism and nexcretion.
2. Pharmacodynamics
are related to the pharmacological nactivity of the interacting drugs e.g synergism.antagonism,
altered cellular transport, effect othe receptor site.
• nPharmacokinetic interactions
1. nAltered GIT absorption
a. nAltered pH
b. nAltered bacterial flora
c. nFormation of drug chelates or complexes
d. nDrug induced mucosal damage and altered GIT motility
Drug nIncompatibility 48
a. nAltered pH:
The nnon-ionized form of a drug is more lipid soluble and more readily absorbed from nGIT than the
ionized nform does.
Therefore, nthese drugs must be separated by at least 2h in the time of administration of nboth .
b. nAltered intestinal bacterial flora
EX., nIn 10% 0f patients receive digoxin…..40% or more of the administered dose is nmetabolized
by nthe intestinal flora.
c. nComplexation or chelation:
Drug nIncompatibility 49
d. nDrug-induced mucosal damage:
e. nAltered motility
2. nDisplaced protein binding
It ndepends on the affinity of the drug to plasma protein. The most likely bound ndrugs is capable to
displace nothers. The free drug is increased by displacement by another drug with higher naffinity.
3. nAltered metabolism
The neffect of one drug on the metabolism of the other is well documented. The liver nis the major
site nof drug metabolism but other organs can also do e.g., WBC, skin, lung, and GIT.
Drug nIncompatibility 50
• nCYP450 family is the major metabolizing enzyme in phase I (oxidation process).
• nTherefore, the effect of drugs on the rate of metabolism of others can involve nthe following
examples:
– nEX1., Enzyme induction:
A ndrug may induce the enzyme that is responsible for the metabolism of another ndrug or even
itself ne.g.,
Carbamazepine n(antiepileptic ndrug ) increases its own metabolism
Phenytoiincreases nhepatic metabolism of theophylline leading to decrease its level
Reduces nits action and Vice versa
Note: nenzyme induction involves protein synthesis .Therefore, it needs time up to 3 nweeks to
reach na maximal effect
– nEX2., Enzyme inhibition
It nis the decrease of the rate of metabolism of a drug by another one. This will nlead to the
increase nof the concentration of the target drug and leading to the increase of its ntoxicity.
Inhibitioof the enzyme may be due to the competition on its binding sites , so the onset nof
actiois short may be within 24h.
N.B; nWhen an enzyme inducer (e.g.carbamazepine) is administered with ainhibitor
(verapamil) nThe effect of the inhibitor will be predominant
– nEx.,Erythromycin inhibit metabolism of astemazole and terfenadine
Increase nthe serum concentration of the antihistaminic agents leading to increasing the nlife
threatening ncardiotoxicity
– nEX., Omeprazole Inhibits oxidative metabolism of diazepam
– nFirst-pass metabolism:
Oral nadministration increases the chance for liver and GIT metabolism of drugs nleading to
the nloss of a part of the drug dose decreasing its action. This is more clear whesuch drug
is nan enzyme inducer or inhibitor.
EX., nrifampin lowers serum concentartion of verapamil level by nincrease its first pass .
Also, nrifampin induces the hepatic metabolism of verapamil.
Drug nIncompatibility 51
4. nAltered renal execration:
a. nInhibition of renal tubular secretion:
• nIt occurs in the proximal tubules (a portion of renal tubules). The drug ncombines with a
specific nprotein to pass through the proximal tubules.
• nWhen a drug has a competitive reactivity to the protein that is responsible for nactive transport
of nanother drug .This will reduce such a drug excretion increasing its nconcentration and hence
its ntoxicity.
• nEX., Probenecid ….. Decreases tubular secretion of methotrexate.
Examples nof drugs that Inhibit renal tubular secretion
Drugs ncausing inhibition Drugs whose t1/2, may be affected
Probenecid
Sulphinpyrazone
Phenylbutazone
Sulphonamides
Aspirin
Thiazide ndiuretics
Indomethacin
Penicillin
Azidothymidine
Indomethacin
Verapamil
Amiodarone
Quinidine
Digoxin
Diuretics nLithium
IndomethaciFrusemide
Aspirin
NSAIDs
Methotrexate
b. nAlteration of urine flow and pH:
• nExcretion and reabsorption (Passive tubular reabsorption) of drugs occur in the ntubules by
passive ndiffusion which is regulated by concentration and lipid solubility.
Note: nIonized drugs are reabsorbed lower thaon-ionized ones
• nLoop and thiazide diuretics indirectly increase proximal tubular reabsorptioof Li+ (which is
handled nin a similar way as Na+) and this can cause Li+ toxicity in patients treated nwith
lithium ncarbonate for mood disorders.
• nThe effect of urinary pH on the excretion of weak acids and bases is put to use nin the treatment
of npoisoning, but is not a cause of accidental interactions.
Drug nIncompatibility 52
• nPharmacodynamic ninteractions
It means alteration of the dug actiowithout change in its serum concentration by pharmacokinetic
factors.
a. Additive effect-occurs whetwo or or more drugs having the same effect are combined and the
result is the sum of the individual neffects relative to the doses used. This additive effect may be
beneficial or harmful to the client.
b. Synergistic effect- occurs nwhen two or more drugs, with or without the same overt effect, are
used together to yield a combined neffect that has an outcome greater than the sum of the singledrugs
active components alone
c. Potentiation-describes a nparticular type of synergistic effect-a drug interaction in which only one
of two drugs exerts the action that is nmade greater by the presence of the second drug.
d. Antagonistic-reactions have nthe opposite effect of synergism and result in a combined effect that
is less than either active component nalone. (eg. Protamine administered as an antidote to
anticoagulant action of heparin)
• nExamples:
– nβ-adrenoceptor antagonists diminish the effectiveness of β-receptor nagonists, such as salbutamol
or nterbutaline.
Drug nIncompatibility 53
– nMany diuretics lower plasma potassium concentration, and thereby enhance some nactions of
digoxiand predispose to glycoside toxicity.
– nMonoamine oxidase inhibitors increase the amount of norepinephrine stored inoradrenergic
nerve nterminals and thereby interact dangerously with drugs, such as ephedrine or ntyramine that
work nby releasing stored norepinephrine. This can also occur with tyramine-rich nfoods—
particularly nfermented cheeses such as Camembert.
– nWarfarin competes with vitamin K, preventing hepatic synthesis of various ncoagulation factors. If
vitamiK production in the intestine is inhibited (e.g. by antibiotics), the nanticoagulant action
of nwarfarin is increased. Drugs that cause bleeding by distinct mechanisms (e.g. naspirin, which
inhibits nplatelet thromboxane A2 biosynthesis and can damage the stomach) increase the nrisk of
bleeding ncaused by warfarin.
– nSulphonamides prevent the synthesis of folic acid by bacteria and other nmicroorganisms;
trimethoprim ninhibits its reduction to tetrahydrofolate. Given together the drugs have a nsynergistic
actioof value in treating Pneumocystis carinii.
– nNon-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or nindomethacin, inhibit
biosynthesis nof prostaglandins, including renal vasodilator/natriuretic prostaglandins n(PGE2,
PGI2). nIf administered to patients receiving treatment for hypertension, they cause a nvariable but
sometimes nmarked increase in blood pressure, and if given to patients being treated with ndiuretics
for nchronic heart failure can cause salt and water retention and hence cardiac ndecompensation.
Note: nThe interaction with diuretics may involve a pharmacokinetic interaction iaddition to the
pharmacodynamic neffect described here, because NSAIDs can compete with weak acids, including
diuretics, nfor renal tubular secretion
– nH1-receptor antagonists, such as mepyramine, commonly cause drowsiness as aunwanted effect.
This nis more troublesome if such drugs are taken with alcohol, and may lead to naccidents at work
or non the road.
Drug nIncompatibility 54
Physical nIncompatibility
Physical nincompatibilities are often called pharmaceutical incompatibilities.
Def.: nInteraction between two or more substances which lead to change in color, odor, ntaste, viscosity and
morphology.
• nManifestations of physical incompatibility:
The nfollowing list outlines the various ways incompatibility between or among drug nagents
may nbe manifested.
1. nInsolubility of prescribed agent in vehicle
2. nImmiscibility of two or more liquids
3. nLiquification of solids mixed in a dry state (called eutexia)
1. nInsolubility:
The nfollowing factors affect the solubility of prescribed agent in vehicle and may nrender it less
soluble:
1. nChange in pH
2. nMilling
3. nSurfactant
4. nChemical reaction
5. nComplex formation
6. nCo-solvent
Any nchange in previous factors may lead to precipitation of drugs and change itheir properties.
Example n1:
Rx
Benzalkonium nchloride
Sodium nlauryl sulfate
They nare not mixed together because benzalkonium chloride is positive charged while nsodium
lauryl nsulfate has negative charge.
By nmixing together a precipitate is formed.
Drug nIncompatibility 55
2. nImmiscibility of two or more liquids
• nThis manifestation appears clearly in emulsion, creams, lotions, some types of nointments.
• nSeparation in two phases is noticed in these pharmaceutical dosage forms.
• nThe following factors lead to immiscibility:
1. nIncomplete mixing
2. nAddition of surfactant with:
– nUnsuitable concentration
– nFalse time of addition
– nUnsuitable for the type of emulsion
3. nPresence of microorganisms
– nSome bacteria grow on constituents of mixture i.e. gelatin Arabic gum
– nOthers produce enzymes which oxidize the surfactant
4. nTemperature
Storage nmust be in room temperature to prevent separation
3. nLiquification of solids mixed in a dry state (eutexia)
• nDef.: it means that when two solid substances are mixed together, nconversion to a liquid state take
place.
• nIt happens through the following methods:
1. nFormation of liquid mixture: when the solid substance is soluble in another nsolid substance
which nlead to decrease of its melting point and conversion to a liquid in certairatios.
2. nExit of crystalline water: By mixing hydrated crystals and dry crystals, ncrystalline water
diffuse nto dry crystals.
Example n2:
Rx
Ephedrine nsulfate
Menthol
Liquid nparaffin
This nprescription is not prescribed because ephedrine sulfate is a salt which is nsoluble in water but
insoluble nin organic solvents, oil and paraffin.
Drug nIncompatibility 56
Chemical nIncompatibility
• nDef.: Reaction between two or more substances which lead to nchange in chemical properties of
pharmaceutical ndosage form.
• nTypes of chemical changes:
1. nOxidation
2. nHydrolysis
3. nPolymerization
4. nIsomerization
5. nDecarboxylation
6. nAbsorption of Co2
7. nCombination
8. nFormation of insoluble complexes
1. nOxidation:
Def.: nOxidation is defined as loss of electrons or gain of oxygen
Auto-oxidation: nIt is a reaction with oxygen of air which occur spontaneously without other
factors.
Pre-oxidants: nare substances catalyze oxidation process i.e. metals, some impurities.
• nFactors lead to oxidation:
1. nPresence of oxygen
2. nLight: it can cause photo-chemical reactions: chemical reaction occur ipresence of light
3. nTemperature: elevated temperature accelerate oxidation reaction
4. nPH: each drug has its ideal pH for stability. Any change in pH affect drug nstability and
may naccelerate oxidation reaction
5. nPharmaceutical dosage form: oxidation reaction occur in solutions faster thain solid
dosage nforms
6. nPresence of pre-oxidants as metals and peroxides
7. nType of solvent used: oxidation reaction occur faster in aqueous solution thaothers.
8. nPresence of unsaturated bonds : as double and triple bonds (oils) which undergo neasier
thasaturated bonds (margarine) for oxidation.
Drug nIncompatibility 57
• nProtection of drugs from oxidation:
1. nAddition of Antioxidants: Vitamin E, vitamin C and inorganic sulfur compounds:
thiosulfate nand polysulfide
2. nAddition of chemicals which form complexes with metals i.e. EDTA, Benzalkonium
chloride
3. nProtection from light:
a. nUsing of dark container
b. nStorage in dark places
c. nPackaging with substances which absorbed light i.e. Oxybenzene
4. nChoice of suitable pharmaceutical dosage forms which reduce the possibility of noxidation
process n(solid dosage forms are better than solutions)
5. nMaintenance of pH by using buffer solution
6. nchoice of suitable solvent (rather than water)
7. nStorage in low temperature
8. nprotection from air by:
a. nusing good closed containers
b. nReplacement of oxygen by nitrogen
• nChemical groups which undergo oxidation:
1. nPhenolic compounds: Phenylephrine
2. nCatechol derivatives: Adrenaline and noradrenaline
3. nSome antibiotics: Tetracyclines
4. nOils (fixed and volatile)
5. nVitamins (lipid and water soluble)
• nHow to identify oxidation in pharmaceutical dosage form?
1. nChange of color, odor, viscosity of dosage form
2. nFor fixed and volatile oils: change of color, taste, odor, and viscosity
2. nHydrolysis:
• nDef.: A chemical reaction in which water is used to break down a ncompound; this is achieved
by nbreaking a covalent bond in the compound by inserting a water molecule across nthe bond
Drug nIncompatibility 58
• nTypes of hydrolysis:
1. nIonic hydrolysis:
– nIn which the compound is broken into ions by water.
– nThe covalent bond between ions of compound is broken down.
– nIt is reversible Ex: Codeine phosphate Codeine + Phosphate
– nThis type take place spontaneously
– nMost affected are weak bases and salts.
2. nMolecular hydrolysis:
– nIn which the molecule it self is broken down.
– nIt is slow process and irreversible.
– nIt must be avoided.
– nEx.: Acetylsalicylic acid Salicylic acid + Acetic acid
– nSo there is no solutions as dosage forms for Aspirin
• nChemical groups which undergo hydrolysis:
1. nEsters:
R-C-OR
Ex: nBenzocaine, Procaine
2. nAmides:
R-C-NH-R
Ex: nChloramphenicol, Sulfonamide, Procainamide
3. nNitriles:
(NO3, nN2O, NO2)
• nFactors induce hydrolysis:
1. nPresence of water
2. npH (Ex. Atropine: optimal pH=3.1-4.5)
3. nHigh temperature (Problem by autoclave i.e. procaine)
H2O
O
O
Drug nIncompatibility 59
Heat
• nProtection from hydrolysis:
1. nProtection from moisture by :
– nPackaging with substances impermeable for moisture
– nAddition of substances that absorb water (CaCO3)
2. nUsing of solvent rather than water
3. nMaintenance of pH by using buffer system
4. nFormation of complexes: which protect the drug from the effect of water
5. nUsing of surfactants (micelle formation)
6. nReducing of solubility of substance (i.e. Suspension instead of solution)
3. nPolymerization:
• nIn polymerization, small repeating units called monomers are bonded to form a nlong chain
polymer.
• nEx:
– nFormaldehyde Paraformaldehyde (Polymer: white precipitate )
To navoid this formaldehyde must be stored in suitable temperature and addition of
methanol n15%.
– nAmpicillin in high temperature forms polymers which cause allergy.
• nFactors induce Polymerization:
1. nTemperature
2. nLight
3. nSolvent
4. npH
5. nImpurities
Drug nIncompatibility 60
A
Autoclaving
A
4. nIsomerization:
• nIt means conversion of drug to its isomer
• nIsomers have:
– nIdentical molecular formulas.
– nA different arrangement of atoms.
• nTypes of isomerization:
a. nOptical isomerization:
– nConversion of optical active drug into less active
– nEx:
a. nL-Adrenaline is converted to d-adrenaline by change of pH or temperature
b. nL-adrenaline is more therapeutically active than d-adrenaline, a although nthey have the
same nphysical properties but different arrangement of atoms.
c. nThis is not general for other drugs: d-tubocurarine is more active thal-type
– nFactors affect optical isomerization :
1. nTemperature
2. npH
3. nSolvent
4. nImpurities
b. nGeometric isomerization:
– nOne type of isomers
– nExpressed by cis or trans
– nCis: means the groups A in the same direction: C C
– nTrans: means the group A in opposite direction :C C
– nCis is more therapeutically active than trans (ex.: Vitamin A)
5. nDecarboxylation:
– nEx.:
NaHCO3 nNa + CO2
All ndrugs contain bicarbonate are not sterilized in high temperature
Drug nIncompatibility 61
– nThe factors that cause decarboxylation are the same as described previously.
6. nCO2 – absorption:
– nWhen some pharmaceutical dosage forms contain CO2, precipitate is formed:
– nEx:
Ca(OH)2 n+ CO2 CaCO3
7. nCombination:
– nTake place when the pharmaceutical dosage form contain substances with ndifferent charges
– nEx.: Surfactants with positive and negative charges
8. nFormation of insoluble complexes:
Ex.: Tetracycline + heavy metals
PHARMACEUTICAL INCOMPATIBILITY n
OBJECTIVES:
At the end of the Lecture students will be able to:
Explain Incompatibility.
Illustrate different examples nof it.
Summarize the importance of nIncompatibility.
Determine ways of detecting nIncompatibility.
Classify the different types nof Incompatibility.
DEFINITION:
Incompatibility nis the result of mixing two or more antagonistic substances as a result of nwhich undesirable product or effect may be seen.
Ways of detecting Incompatibility:
It may be ndetected by:
Ø Physical change.
Ø Chemical change.
Ø Therapeutic change.
Importance Of Determining Incompatibility:
Incompatible nproducts may effect:
Ø Safety of medicament.
Ø Efficacy of product.
Ø Appearance of a medicine.
Ø Purpose of medication.
Types Of Incompatibilities:
Ø Physical incompatibility.
Ø Chemical incompatibility.
Ø Therapeutic incompatibility.
OBJECTIVES:
At the end of the lecture the students will be able nto:
Ø Describe Physical nIncompatibility.
Ø Identify and discuss in detail the causes nof Physical Incompatibility.
Ø Predict the consequences of nPhysical Incompatibility.
Ø Explain briefly techniques may nbe used to rectify the Incompatibility.
nPHYSICAL INCOMPATIBILITY:
When two or more substances are combine ntogether a physical change would takes place leading to an incompatible nproduct.
Consequences
– nFormatioof unsighted product
– nNouniform dosage form
– nRemoval nof Inaccurate dose
– nImproper nTherapeutic effects
nCauses:
Ø Immiscibility
Ø Insolubility
Ø Liquefaction
Immiscibility
What is a miscible solution?
The components of an Ideal solution are nmiscible in all proportions for e.g. water and ethanol, propylene glycol and nwater, propylene glycol and acetone etc.
Examples:
Ø Oil and water .For e.g. Castor noil ,Olive oil.
Ø Concentrated Hydro alcoholic solutions nof volatile oils (spirits and concentrated water)
Methods Of Rectifying Immiscibility:
Immiscibility can be overcome by:
Ø Vigorous shaking / stirring.
Ø Emulsification or solubilization for e.g. Fats soluble Vitamins, nCertain antibiotics like Chloramphenicol, Amphotericin B, Analgesics nlike Aspirin, Acetanilide & phenacetin nmany alkaloids and glycosides etc are made soluble by the ntechnique of solubilization.
OBJECTIVES:
– nExplain briefly the consequences of Insolubility.
– nIllustrate different examples of Insolubility.
– n Define nLiquefaction.
– nIllustrate examples of Liquefaction.
– nInterpret the Manifestation of Physical nIncompatibility.
– nDescribe Therapeutic Incompatibility.
– nIllustrate examples of Therapeutic Incompatibility.
– nInsolubility
n If the amount of the solute is nnot dissolved in a given amount of solvent.
Criteria for determining solubility
Condition Amount Of nSolvent Require To
Dissolve 1 Part Of Solute
Ø Very soluble less than 1 part
Ø Freely soluble 1 – 10 parts
Ø Soluble 10 – 30 nparts
Ø Sparingly soluble 30 – 100 parts
Ø Slightly soluble 100 – 1000 parts
Ø Very slightly soluble 1000 – 10,000 parts
Ø Practically insoluble More than 10,000 parts
Examples Of Insoluble nCombinations:
Ø Some in diffusible solids such nas Chalk, Aspirin, Phenobarbitone, Succinyl nsulphathiazole etc
Ø Some Antibiotics like Cortisone Acetate, Hydrocortisone nAcetate, Procaine benzyl penicillin.
Ø Constituents of alcoholic nvegetable drugs may precipitate when the solvent is changed (On addition of nwater). For e.g. tinctures of Belladonna and hyoscyamus.
Ø Resinous tincture is nprecipitated when added to water. For e.g. Myrrh Tincture.
Methods Of Rectifying nInsolubility:
Ø Co solvency : for e.g. we may use alcohol, npropylene glycol, syrups.
Ø Complexation: for e.g. formation of tri iodide complex , complexatioof caffeine with Sodium Benzoate.
Ø Hydro trophy: for e.g. Hyoscamine with tween .
Ø Solubilization: for e.g. Fats soluble nvitamins, certain antibiotics.
LIQUEFACTION
It is the condition in which we mix the two powders of nlower melting point so the mixture get liquefy due to the formation of eutectic nmixture .
Examples:
Camphor ,menthol, phenol, thymol ,chloral nhydrate, sodium salicylate,Aspirin , phenazone.
Methods Of Rectifying nLiquefaction:
By the nuse of absorbent like kaolin, light magnesium carbonate.
Techniques to Rectify:
Ø Order of mixing.
Ø Alteration of solvent.
Ø Change in the form of ningredients.
Ø Alteration of volume.
Ø Emulsification.
Ø Addition of suspending agents.
Ø Addition/Substitution/omissioof therapeutically inactive substance.
Practical examples of nprescriptions:
Rx
Olive oil 30 nml
Ø Water up to n120 ml
Directions for Pharmacist:
Make an emulsion.
Comments:
Physical incompatibility.
Rx
Phenacetin 3 gm
Caffeine 1 gm
Orange syrup 12 ml
Water up to 90 ml
Directions for Pharmacist:
Make a mixture. Send 25 ml
Comments:
Physical incompatibility.
Rx
Menthol n5 gm
Camphor n5 gm
Ammonium chloride 30 gm
Light magnesium carbonate 60 gm
Directions for Pharmacist:
Make aInsufflations. Send 40 gm.
Comments:
Correct prescription.
THERAPEUTIC INCOMPATIBILITY
It may be the result of prescribing certaidrugs to the patient with the intention to produce a specific degree of actiobut the nature or the intensity of the action produced is different from that nintended by the prescriber.
CAUSES:
It may be due to the administration of n:
Overdose or improper dose of a nsingle drug.
Improper Dosage form.
Contraindicated drug.
Synergistic and antagonistic ndrugs.
Rx
Codeine phosphate
0.6 gms
Directions for Pharmacist:
Make powders.
Send such 10 powders.
Comments:
Therapeutic incompatibility.
Rx
Tetracycline Hydrochloride
250 gms
Directions for Pharmacist:
Make nCapsules.
Send 10 such ncapsules.
Label:
Take 10 ncapsules every six hours with milk.
Comments:
Therapeutic incompatibility.
Rx
Amphetamine Sulphate 20 mg
Ephedrine Sulphate 100 mg
Simple syrup up to 100 ml.
Directions for Pharmacist:
Make a mixture.
Comments:
Therapeutic incompatibility.
Rx
Acetophenatidine 150 mg
Acetyl Salicylic Acid 200 mg
Caffeine 40 mg
Directions for Pharmacist:
Make Capsules. Send such 10 capsules.
Comments:
Correct prescription. Therapeutic nincompatibility but Intentional.
Occasionally the pharmacist is called upon to fill a prescription that ncan’t satisfactorily and safely dispense unless the corrective measures are ntaken. He is then faced the problems of incompatibility. The term nincompatibility may be applied to the pharmaceuticals when problem arises nduring their compounding, dispensing or administration. Incompatibilities were nfrequent in earlier days when the prescription contains multiple ingredients. nThe modern trained towards simple prescription with only one or 2 specific nmedicines have reduced the frequency but not the important of incompatibility nand the pharmacist of today must still check all prescription carefully. The ndetection and correction of incompatibility is the responsibility and duty of nevery pharmacist. The primary function of physician is to diagnose and to nprescribe and that of pharmacist is to compound and dispense a therapeutically neffective medication. A very important ingredient of all the prescription is nthe skill with which they are compounded and this is particularly true iprescription originally containing an incompatibility. The most important step nin dealing with incompatibility is recognizing by noting an incompatibility nbefore aprescription is filled. The pharmacist can take corrective measures nthat save both time and material. It is easier to prevent an incompatibility nrather than to correct it. An incompatibility is not recognized until after the nprescription has been compounded. The prescription should not be dispensed nuntil the incompatibility has been corrected. If the trouble can be remetide(remove) in the filled prescription, this is npermissible but rather than dispense an incompatible product, the pharmacist nshould discard prescription and fill it again in a manner that correct the nincompatibility. It is important to remember that prescription written today ndoes not contain incompatibilities and that the incompatibilities are the nexception rather than the rule. The pharmacist should never exaggeration the nsituation and find imaginary difficulties where none really exist, eg, a ncombination of drug which yield precipitates or effervescence on mixing does nnot necessarily mean that aprescription contain an incompatibility.
Example of prescription:
Zinc Sulfate……………. 4
Potassium sulfate …… Glycerin…………………5
Aqua rosa ………………q.s to make 120ml
Direction for pharmacist: MFT lotion (MFT: MANUFACTURE).
The pharmacist should recognize the type of formula in this prescriptioand understand that the prescriber wants the precipitates that will form whesolution of zinc sulfate and potassium sulfate are mixed together. Infect the ntherapeutic value of the preparation depends upon this precipitates and the nprescription should be filled as it is written. Similarly most prescription for nmixtures, suspensions and liquid preparation containingin soluble material nshould not be considered as having incompatibility.
Type of incompatibilities:
1. Physical incompatibility
2. Chemical incompatibility
3. Therapeutic incompatibility
A combination of above type also exist and inter-relationship may nalso exist among them and in many situations they can’tbe separated. It is also npossible for a single prescription to contain more than 1 incompatibility. Although the occurrence of this nature are rare. It isalso possible for a pharmacist to introduce in a prescriptiodifferent incompatibilities in the process of eliminating. Thus before nany corrective measures are taken, the pharmacist should assure himself that a nfinal product will be satisfactory in all aspects.
Physical incompatibility:
It is of various types.
- Incomplete solution:
n
When 2 or more substances are combined they doot give homogenous product ndue to immiscibility or insolubility.
Example:
silicon is immiscible with water, ngums are insoluble in alcohol, resins are insoluble in water.
Example of prescription:
Terpine hydrate ……………… 3g
Simple syrup ………………… q.s tomake 120ml
MFT solution.
Terpine hydrate is insoluble in simple syrup then how we make solution? So nin this case ½ of the syrup may be replace by alcohol or iso-alcohlic nelixirs or the drug may be suspended with accasia tragacanth and dispense with na shake label.
Methods for correction/prevention of physical nincompatibility
Modified order of mixing:
This method will vary often to overcome certain type of physical nincompatibility. So this should be considered first.
Example if salt is not soluble in alcohol, prescribed in hydro alcoholic nliquids. So we dissolve salt first in water and then this solution should be nmixed with the liquid prescribed.
Example:
alcohol soluble substances to be dispensed nin hydro alcoholic liquids. First dissolve in small amount of alcohol, themixed with the prescribed solution. A general rule is to dissolve the nprescribed substance first in the solvent in which it is most soluble and theadd to this solution slowly with constant stirring so as to effect the gradual ndilution in the liquid in which it is least soluble.
Example of prescription:
Magnesium carbonate ……….. 3.75g
Citric acid ……………………. 7.5g
Sodium bicarbonate …………. 7.5g
Boiled water ………………… q.s to make 250ml
MFT solution or MFT citrate solution.
Magnesium carbonate is insoluble and will react with citricacid to from nmagnesium citrate in solution. Sodium bicarbonate is soluble in liquid. If ncitric acid is dissolved first in water and then sodium bicarbonateis added to nthis solution and after that magnesium carbonate is added. A cleanand complete nsolution is not produced, since some of the magnesium carbonate will remaiunchanged. On the other hand a perfectly clean solution can be obtained by nadding the magnesium carbonate to the solution of citric acid first and allow nthese 2 compounds to react completely to form solution of magnesium citrate and nthen adding the sodium bicarbonate. The reason for this order of mixing is that nboth magnesium carbonate and sodium bicarbonate will react with citric acid isolution. When bicarbonate ion is added first it uses some of citric acid so nthat not enough is left to convert all the magnesium carbonate to solubilize nmagnesium citrate. As a result the carbonate that is left will not dissolve by nreacting the magnesium carbonate and citric acid. First all ofthe carbonate is nconverted to the citrate then the sodium bicarbonate which is water soluble is nadded to give a clean solution.
Alternate of solvents:
Solvents can be altered but to alimited extent.
Example:
an alcohol soluble drug may be prescribed in elixir that ndoes not have sufficient concentration of the alcohol to hold it insolution. It nis then allowed to increase alcoholic concentration with in reasonable limit. nSo long as the volume of the prescription is not changed.
Alcohol: it is a good solvent for many organic compounds such nas alkaloid, camphor, phenol, tannins, balsams, resins and some other organic nacids.
Glycerin: it has solvent properties between those of alcohol nand water. It is particularly good for dissolving tannins, boric acid, phenols,codeine and certain metallic salts.
Example of alternate solvents to prepare clear solution is given by nfollowing prescription.
Alcohol ………………….. 15ml
Terpine hydrate …………. 2gm
Glycerin ………………… 20ml
Wild cherry syrup ………. Q.s to make 60ml
MFT solution.
The prescription if filled as written will not give a clear solution. The nalcohol concentration is not high enough to hold all the terpinehydrate isolution and small crystal settle out. This condition can be corrected by nadjusting the alcohol concentration to 40%, which is same as that of the nofficial terpine hydrate elixir.
Changing the form of ingredients:
A change in the form of the ingredients is often unable to obtain a better npreparation. However it should be clearly understand that this action is napplicable only when the therapeutic action of ingredientis not altered.
Example of prescription:
Phenobarbital …………….. gr vii (7 gran)
Sodium salicylate ………… z I (1dram)
Aqua mentha preparata …… q.s to make z ii (2 ounce)
Phenobarbital is insoluble in aqueous solution. Sodium slat of nPhenobarbital, which has the same action and the same dose, may be used inits nplace to obtain a clear solution.
Drug nIncompatibility
• nDefinition of Drug Incompatibility:
Drug nIncompatibility refers to interactions between two or more substances which nlead to changes in
chemical, nphysical, therapeutic properties of the pharmaceutical dosage form.
• nTypes of Drug Incompatibility
1. nTherapeutic incompatibility
2. nPhysical incompatibility
3. nChemical incompatibility
1. nTherapeutic incompatibility
• nDefinition of Therapeutic incompatibility
It nis the modification of the therapeutic effect of one drug by the prior nconcomitant administration of
another. n(It is also called drug interactions)
• nMechanisms of therapeutic incompatibility
They nare divided into two groups:
1. nPharmacokinetics:
involve nthe effect of a drug on another from the point of view that includes absorption
,distributio, metabolism and excretion.
2. nPharmacodynamics
are nrelated to the pharmacological activity of the interacting drugs e.g nsynergism.antagonism,
altered ncellular transport, effect on the receptor site.
• nPharmacokinetic interactions
1. nAltered GIT absorption
a. nAltered pH
b. nAltered bacterial flora
c. nFormation of drug chelates or complexes
d. Drug induced mucosal damage and naltered GIT motility
a. nAltered pH:
The nnon-ionized form of a drug is more lipid soluble and more readily absorbed from nGIT than the
ionized form does.
Therefore, nthese drugs must be separated by at least 2h in the time of administration of nboth .
b. nAltered intestinal bacterial flora
EX., nIn 10% 0f patients receive digoxin…..40% or more of the administered dose is nmetabolized
by nthe intestinal flora.
c. Complexation
c. Complexation or chelation:
d. Drug-induced mucosal damage:
e. Altered motility
2. nDisplaced protein binding
It ndepends on the affinity of the drug to plasma protein. The most likely bound ndrugs is capable to
displace nothers. The free drug is increased by displacement by another drug with higher naffinity.
3. nAltered metabolism
The neffect of one drug on the metabolism of the other is well documented. The liver nis the major
site of drug metabolism but other organs ncan also do e.g., WBC, skin, lung, and GIT.
CYP450 nfamily is the major metabolizing enzyme in phase I (oxidation process).
• nTherefore, the effect of drugs on the rate of metabolism of others can involve nthe following
examples:
– nEX1., Enzyme induction:
A ndrug may induce the enzyme that is responsible for the metabolism of another ndrug or even
itself ne.g.,
Carbamazepine n(antiepileptic ndrug ) increases its own metabolism
Phenytoiincreases nhepatic metabolism of theophylline leading to decrease its level –
Reduces nits action and Vice versa
Note: nenzyme induction involves protein synthesis .Therefore, it needs time up to 3 nweeks to
reach na maximal effect
– nEX2., Enzyme inhibition
It nis the decrease of the rate of metabolism of a drug by another one. This will nlead to the
increase nof the concentration of the target drug and leading to the increase of its ntoxicity.
Inhibitioof the enzyme may be due to the competition on its binding sites , so the onset nof
actiois short may be within 24h.
N.B; nWhen an enzyme inducer (e.g.carbamazepine) is administered with ainhibitor
(verapamil) – The effect of the ninhibitor will be predominant
– nEx.,Erythromycin inhibit metabolism of astemazole and terfenadine
Increase nthe serum concentration of the antihistaminic agents leading to increasing the nlife
threatening ncardiotoxicity
– nEX., Omeprazole Inhibits oxidative metabolism of diazepam
– nFirst-pass metabolism:
Oral nadministration increases the chance for liver and GIT metabolism of drugs nleading to
the nloss of a part of the drug dose decreasing its action. This is more clear whesuch drug
is nan enzyme inducer or inhibitor.
EX., nrifampin lowers serum concentartion of verapamil level by nincrease its first pass .
Also, rifampin induces the nhepatic metabolism of verapamil.
4. nAltered renal execration:
a. nInhibition of renal tubular secretion:
• nIt occurs in the proximal tubules (a portion of renal tubules). The drug ncombines with a
specific nprotein to pass through the proximal tubules.
• nWhen a drug has a competitive reactivity to the protein that is responsible for nactive transport
of nanother drug .This will reduce such a drug excretion increasing its concentratioand hence
its ntoxicity.
• EX., Probenecid ….. Decreases ntubular secretion of methotrexate.
|
Examples of drugs that Inhibit renal tubular secretion |
|
|
Drugs causing inhibition |
Drugs whose t1/2, may be affected |
|
Probenecid Sulphinpyrazone Phenylbutazone Sulphonamides Aspirin Thiazide diuretics Indomethacin |
Penicillin Azidothymidine Indomethacin |
|
Verapamil Amiodarone Quinidine |
Digoxin |
|
Diuretics |
Lithium |
|
Indomethacin |
Frusemide |
|
Aspirin NSAIDs |
Methotrexate |
b. nAlteration of urine flow and pH:
• nExcretion and reabsorption (Passive tubular reabsorption) of drugs occur in the ntubules by
passive ndiffusion which is regulated by concentration and lipid solubility.
Note: nIonized drugs are reabsorbed lower thaon-ionized ones
• nLoop and thiazide diuretics indirectly increase proximal tubular reabsorptioof Li+ (which is
handled nin a similar way as Na+) and this can cause Li+ toxicity in patients treated nwith
lithium ncarbonate for mood disorders.
• nThe effect of urinary pH on the excretion of weak acids and bases is put to use nin the treatment
of poisoning, but is not a cause of naccidental interactions.
Pharmacodynamic ninteractions
It nmeans alteration of the dug action without change in its serum concentration by npharmacokinetic
factors.
a. nAdditive effect-occurs when two or or more drugs having the same effect nare combined and the
result nis the sum of the individual effects relative to the doses used. This additive neffect may be
beneficial nor harmful to the client.
b. nSynergistic effect- occurs when two or more drugs, with or without the nsame overt effect, are
used ntogether to yield a combined effect that has an outcome greater than the sum of nthe singledrugs
active ncomponents alone
c. nPotentiation-describes a particular type of synergistic effect-a drug ninteraction in which only one
of ntwo drugs exerts the action that is made greater by the presence of the second ndrug.
d. nAntagonistic-reactions have the opposite effect of synergism and result nin a combined effect that
is nless than either active component alone. (eg. Protamine administered as aantidote to
anticoagulant naction of heparin)
• nExamples:
– nβ-adrenoceptor antagonists diminish the effectiveness of β-receptor nagonists, such as salbutamol
or terbutaline.
Many ndiuretics lower plasma potassium concentration, and thereby enhance some nactions of
digoxiand predispose to glycoside toxicity.
– nMonoamine oxidase inhibitors increase the amount of norepinephrine stored inoradrenergic
nerve nterminals and thereby interact dangerously with drugs, such as ephedrine or ntyramine that
work nby releasing stored norepinephrine. This can also occur with tyramine-rich nfoods—
particularly nfermented cheeses such as Camembert.
– nWarfarin competes with vitamin K, preventing hepatic synthesis of various ncoagulation factors. If vitamiK production in the intestine is inhibited (e.g. by antibiotics), the nanticoagulant action
of nwarfarin is increased. Drugs that cause bleeding by distinct mechanisms (e.g. naspirin, which
inhibits nplatelet thromboxane A2 biosynthesis and can damage the stomach) increase the nrisk of
bleeding ncaused by warfarin.
– nSulphonamides prevent the synthesis of folic acid by bacteria and other nmicroorganisms;
trimethoprim ninhibits its reduction to tetrahydrofolate. Given together the drugs have a nsynergistic
actioof value in treating Pneumocystis carinii.
– nNon-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or nindomethacin, inhibit
biosynthesis nof prostaglandins, including renal vasodilator/natriuretic prostaglandins n(PGE2,
PGI2). nIf administered to patients receiving treatment for hypertension, they cause a nvariable but
sometimes nmarked increase in blood pressure, and if given to patients being treated with ndiuretics
for nchronic heart failure can cause salt and water retention and hence cardiac ndecompensation.
Note: nThe interaction with diuretics may involve a pharmacokinetic interaction iaddition to the
pharmacodynamic neffect described here, because NSAIDs can compete with weak acids, including
diuretics, nfor renal tubular secretion
– nH1-receptor antagonists, such as mepyramine, commonly cause drowsiness as aunwanted effect.
This nis more troublesome if such drugs are taken with alcohol, and may lead to naccidents at work
or on the road.
Physical nIncompatibility
Physical nincompatibilities are often called pharmaceutical incompatibilities.
Def.: nInteraction between two or more substances which lead to change in color, odor, ntaste, viscosity and
morphology.
• nManifestations of physical incompatibility:
The nfollowing list outlines the various ways incompatibility between or among drug nagents
may nbe manifested.
1. nInsolubility of prescribed agent in vehicle
2. nImmiscibility of two or more liquids
3. nLiquification of solids mixed in a dry state (called eutexia)
1. nInsolubility:
The nfollowing factors affect the solubility of prescribed agent in vehicle and may nrender it less
soluble:
1. nChange in pH
2. nMilling
3. nSurfactant
4. nChemical reaction
5. nComplex formation
6. nCo-solvent
Any change in previous factors may lead nto precipitation of drugs and change in their properties.
2. nImmiscibility of two or more liquids
• nThis manifestation appears clearly in emulsion, creams, lotions, some types of nointments.
• nSeparation in two phases is noticed in these pharmaceutical dosage forms.
• nThe following factors lead to immiscibility:
1. nIncomplete mixing
2. nAddition of surfactant with:
– nUnsuitable concentration
– nFalse time of addition
– nUnsuitable for the type of emulsion
3. nPresence of microorganisms
– nSome bacteria grow on constituents of mixture i.e. gelatin Arabic gum
– nOthers produce enzymes which oxidize the surfactant
4. nTemperature
Storage nmust be in room temperature to prevent separation
3. nLiquification of solids mixed in a dry state (eutexia)
• nDef.: it means that when two solid substances are mixed together, nconversion to a liquid state take
place.
• nIt happens through the following methods:
1. nFormation of liquid mixture: when the solid substance is soluble in another nsolid substance
which nlead to decrease of its melting point and conversion to a liquid in certairatios.
2. nExit of crystalline water: By mixing hydrated crystals and dry crystals, ncrystalline water
diffuse to dry crystals.
Chemical nIncompatibility
• nDef.: Reaction between two or more substances which lead to nchange in chemical properties of
pharmaceutical ndosage form.
• nTypes of chemical changes:
1. nOxidation
2. nHydrolysis
3. nPolymerization
4. nIsomerization
5. nDecarboxylation
6. nAbsorption of Co2
7. nCombination
8. nFormation of insoluble complexes
1. nOxidation:
Def.: nOxidation is defined as loss of electrons or gain of oxygen
Auto-oxidation: nIt is a reaction with oxygen of air which occur spontaneously without other
factors.
Pre-oxidants: nare substances catalyze oxidation process i.e. metals, some impurities.
• nFactors lead to oxidation:
1. nPresence of oxygen
2. nLight: it can cause photo-chemical reactions: chemical reaction occur ipresence of light
3. nTemperature: elevated temperature accelerate oxidation reaction
4. nPH: each drug has its ideal pH for stability. Any change in pH affect drug nstability and
may naccelerate oxidation reaction
5. nPharmaceutical dosage form: oxidation reaction occur in solutions faster thain solid
dosage nforms
6. nPresence of pre-oxidants as metals and peroxides
7. nType of solvent used: oxidation reaction occur faster in aqueous solution thaothers.
8. nPresence of unsaturated bonds : as double and triple bonds (oils) which undergo neasier
than saturated bonds (margarine) for noxidation.
• nProtection of drugs from oxidation:
1. nAddition of Antioxidants: Vitamin E, vitamin C and inorganic sulfur compounds:
thiosulfate nand polysulfide
2. nAddition of chemicals which form complexes with metals i.e. EDTA, Benzalkonium
chloride
3. nProtection from light:
a. nUsing of dark container
b. nStorage in dark places
c. nPackaging with substances which absorbed light i.e. Oxybenzene
4. nChoice of suitable pharmaceutical dosage forms which reduce the possibility of noxidation
process n(solid dosage forms are better than solutions)
5. nMaintenance of pH by using buffer solution
6. nchoice of suitable solvent (rather than water)
7. nStorage in low temperature
8. nprotection from air by:
a. nusing good closed containers
b. nReplacement of oxygen by nitrogen
• nChemical groups which undergo oxidation:
1. nPhenolic compounds: Phenylephrine
2. nCatechol derivatives: Adrenaline and noradrenaline
3. nSome antibiotics: Tetracyclines
4. nOils (fixed and volatile)
5. nVitamins (lipid and water soluble)
• nHow to identify oxidation in pharmaceutical dosage form?
1. nChange of color, odor, viscosity of dosage form
2. nFor fixed and volatile oils: change of color, taste, odor, and viscosity
2. nHydrolysis:
• nDef.: A chemical reaction in which water is used to break down a ncompound; this is achieved
by breaking a covalent bond in the ncompound by inserting a water molecule across the bond
Types nof hydrolysis:
1. nIonic hydrolysis:
– nIn which the compound is broken into ions by water.
– The covalent bond between ions of ncompound is broken down.
It nis reversible Ex: Codeine phosphate Codeine + Phosphate
– nThis type take place spontaneously
– Most affected are weak bases and nsalts.
2. nMolecular hydrolysis:
– nIn which the molecule it self is broken down.
– nIt is slow process and irreversible.
– nIt must be avoided.
– nEx.: Acetylsalicylic acid Salicylic acid + Acetic acid
– nSo there is no solutions as dosage forms for Aspirin
• nChemical groups which undergo hydrolysis:
1. nEsters:
R-C-OR
Ex: nBenzocaine, Procaine
2. nAmides:
R-C-NH-R
Ex: nChloramphenicol, Sulfonamide, Procainamide
3. nNitriles:
(NO3, nN2O, NO2)
• nFactors induce hydrolysis:
1. nPresence of water
2. npH (Ex. Atropine: optimal pH=3.1-4.5)
3. High temperature (Problem by nautoclave i.e. procaine)
• nProtection from hydrolysis:
1. nProtection from moisture by :
– nPackaging with substances impermeable for moisture
– nAddition of substances that absorb water (CaCO3)
2. nUsing of solvent rather than water
3. nMaintenance of pH by using buffer system
4. nFormation of complexes: which protect the drug from the effect of water
5. nUsing of surfactants (micelle formation)
6. nReducing of solubility of substance (i.e. Suspension instead of solution)
3. nPolymerization:
• nIn polymerization, small repeating units called monomers are bonded to form a nlong chain
polymer.
• nEx:
– nFormaldehyde Paraformaldehyde (Polymer: white precipitate )
To navoid this formaldehyde must be stored in suitable temperature and addition of
methanol n15%.
– nAmpicillin in high temperature forms polymers which cause allergy.
• nFactors induce Polymerization:
1. nTemperature
2. nLight
3. nSolvent
4. npH
5. Impurities
4. nIsomerization:
• nIt means conversion of drug to its isomer
• nIsomers have:
– nIdentical molecular formulas.
– nA different arrangement of atoms.
• nTypes of isomerization:
a. nOptical isomerization:
– nConversion of optical active drug into less active
– nEx:
a. nL-Adrenaline is converted to d-adrenaline by change of pH or temperature
b. nL-adrenaline is more therapeutically active than d-adrenaline, a although nthey have the
same nphysical properties but different arrangement of atoms.
c. nThis is not general for other drugs: d-tubocurarine is more active thal-type
– nFactors affect optical isomerization :
1. nTemperature
2. npH
3. nSolvent
4. nImpurities
b. nGeometric isomerization:
– nOne type of isomers
– nExpressed by cis or trans
– nCis: means the groups A in the same direction: C C
– nTrans: means the group A in opposite direction :C C
– nCis is more therapeutically active than trans (ex.: Vitamin A)
5. nDecarboxylation:
– Ex.:
The nfactors that cause decarboxylation are the same as described previously.
6. nCO2 – absorption:
– nWhen some pharmaceutical dosage forms contain CO2, precipitate is formed:
– Ex:
7. nCombination:
– nTake place when the pharmaceutical dosage form contain substances with ndifferent charges
– nEx.: Surfactants with positive and negative charges
8. nFormation of insoluble complexes:
Ex.: Tetracycline + heavy metals
Incompatibility
Occasionally nthe pharmacist is called upon to fill a prescription that can’t satisfactorily nand safely dispense unless the corrective measures are taken. He is then faced nthe problems of incompatibility. The term incompatibility may be applied to the npharmaceuticals when problem arises during their compounding, dispensing or nadministration. Incompatibilities were frequent in earlier days when the nprescription contains multiple ingredients. The modern trained towards simple nprescription with only one or 2 specific medicines have reduced the frequency nbut not the important of incompatibility and the pharmacist of today must still ncheck all prescription carefully. The detection and correction of nincompatibility is the responsibility and duty of every pharmacist. The primary nfunction of physician is to diagnose and to prescribe and that of pharmacist is nto compound and dispense a therapeutically effective medication. A very nimportant ingredient of all the prescription is the skill with which they are ncompounded and this is particularly true in prescription originally containing nan incompatibility. The most important step in dealing with incompatibility is nrecognizing by noting an incompatibility before aprescription is filled. The npharmacist can take corrective measures that save both time and material. It is neasier to prevent an incompatibility rather than to correct it. Aincompatibility is not recognized until after the prescription has beecompounded. The prescription should not be dispensed until the incompatibility nhas been corrected. If the trouble can be remetide(remove) in the filled nprescription, this is permissible but rather than dispense an incompatible nproduct, the pharmacist should discard prescription and fill it again in a nmanner that correct the incompatibility. It is important to remember that nprescription written today does not contain incompatibilities and that the nincompatibilities are the exception rather than the rule. The pharmacist should nnever exaggeration the situation and find imaginary difficulties where none nreally exist, eg, a combination of drug which yield precipitates or neffervescence on mixing does not necessarily mean that aprescription contain aincompatibility.
Example of nprescription:
nZinc Sulfate……………. 4
nPotassium sulfate …… n nGlycerin…………………5
nAqua rosa ………………q.s to make 120ml
Direction for npharmacist: MFT lotion (MFT: MANUFACTURE).
The pharmacist should nrecognize the type of formula in this prescription and understand that the nprescriber wants the precipitates that will form when solution of zinc sulfate nand potassium sulfate are mixed together. Infect the therapeutic value of the npreparation depends upon this precipitates and the prescription should be nfilled as it is written. Similarly most prescription for mixtures, suspensions nand liquid preparation containingin soluble material should not be considered nas having incompatibility.
Type of nincompatibilities:
1. nPhysical nincompatibility
2. nChemical nincompatibility
3. nTherapeutic nincompatibility
A combination of nabove type also exist and inter-relationship may also exist among them and imany situations they can’tbe separated. It is also possible for a single nprescription to contain more than 1 incompatibility. Although the occurrence of nthis nature are rare. It isalso possible for a pharmacist to introduce in a nprescription different incompatibilities in the process of eliminating. Thus nbefore any corrective measures are taken, the pharmacist should assure himself nthat a final product will be satisfactory in all aspects.
Physical nincompatibility:
nIt is of various types.
· Incomplete solution:
nWhen 2 or more substances are combined they doot give homogenous product due nto immiscibility or insolubility.
Example:
silicon is immiscible nwith water, gums are insoluble in alcohol, resins are insoluble in water.
Example of nprescription:
nTerpine hydrate ……………… 3g
nSimple syrup ………………… q.s tomake 120ml
nMFT solution.
Terpine hydrate is ninsoluble in simple syrup then how we make solution? So in this case ½ nof the syrup may be replace by alcohol or iso-alcohlic elixirs or the drug may nbe suspended with accasia tragacanth and dispense with a shake label.
Methods for ncorrection/prevention of physical incompatibility
Modified order of nmixing:
This method will vary noften to overcome certain type of physical incompatibility. So this should be nconsidered first.
Example if salt is nnot soluble in alcohol, prescribed in hydro alcoholic liquids. So we dissolve nsalt first in water and then this solution should be mixed with the liquid nprescribed.
Example:
alcohol soluble nsubstances to be dispensed in hydro alcoholic liquids. First dissolve in small namount of alcohol, then mixed with the prescribed solution. A general rule is to ndissolve the prescribed substance first in the solvent in which it is most nsoluble and then add to this solution slowly with constant stirring so as to neffect the gradual dilution in the liquid in which it is least soluble.
Example of nprescription:
nMagnesium carbonate ……….. 3.75g
nCitric acid ……………………. 7.5g
nSodium bicarbonate …………. 7.5g
nBoiled water ………………… q.s to make 250ml
MFT solution or MFT ncitrate solution.
Magnesium carbonate nis insoluble and will react with citricacid to from magnesium citrate isolution. Sodium bicarbonate is soluble in liquid. If citric acid is dissolved nfirst in water and then sodium bicarbonateis added to this solution and after nthat magnesium carbonate is added. A cleanand complete solution is not nproduced, since some of the magnesium carbonate will remain unchanged. On the nother hand a perfectly clean solution can be obtained by adding the magnesium ncarbonate to the solution of citric acid first and allow these 2 compounds to nreact completely to form solution of magnesium citrate and then adding the nsodium bicarbonate. The reason for this order of mixing is that both magnesium ncarbonate and sodium bicarbonate will react with citric acid in solution. Whebicarbonate ion is added first it uses some of citric acid so that not enough nis left to convert all the magnesium carbonate to solubilize magnesium citrate. nAs a result the carbonate that is left will not dissolve by reacting the nmagnesium carbonate and citric acid. First all ofthe carbonate is converted to nthe citrate then the sodium bicarbonate which is water soluble is added to give na clean solution.
Alternate of nsolvents:
nSolvents can be altered but to alimited extent.
Example:
an alcohol soluble ndrug may be prescribed in elixir that does not have sufficient concentration of nthe alcohol to hold it insolution. It is then allowed to increase alcoholic nconcentration with in reasonable limit. So long as the volume of the nprescription is not changed.
Alcohol: it is a good solvent for many organic compounds such nas alkaloid, camphor, phenol, tannins, balsams, resins and some other organic nacids.
Glycerin: it has solvent properties between those of alcohol nand water. It is particularly good for dissolving tannins, boric acid, nphenols,codeine and certain metallic salts.
Example of alternate nsolvents to prepare clear solution is given by following prescription.
nAlcohol ………………….. 15ml
nTerpine hydrate …………. 2gm
nGlycerin ………………… 20ml
nWild cherry syrup ………. Q.s to make 60ml
nMFT solution.
The prescription if nfilled as written will not give a clear solution. The alcohol concentration is nnot high enough to hold all the terpinehydrate in solution and small crystal nsettle out. This condition can be corrected by adjusting the alcohol nconcentration to 40%, which is same as that of the official terpine hydrate nelixir.
Changing the form of ningredients:
nA change in the form of the ingredients is often unable to obtain a better npreparation. However it should be clearly understand that this action is napplicable only when the therapeutic action of ingredientis not altered.
Example of nprescription:
nPhenobarbital …………….. gr vii (7 gran)
nSodium salicylate ………… z I (1dram)
nAqua mentha preparata …… q.s to make z ii (2 ounce)
Phenobarbital is ninsoluble in aqueous solution. Sodium slat of Phenobarbital, which has the same naction and the same dose, may be used inits place to obtain a clear solution.
Introduction:
nIncompatibility refers to the inability of something or some process to nco-exist with another process or thing.
So, Pharmaceutical incompatibility refers to the inability of a npharmaceutical substance to exist in combination with another pharmaceutical nentity.
Types nof Incompatibility:
There nare three types of incompatibility:
1. nTherapeutical incompatibility
2. nChemical incompatibility
3. nPharmaceutical or physical incompability
1. nTherapeutical incompatibility:
This nincompabitlity is resulted due to the combination of drugs having antagonistic nor opposing properties.
n2. Chemical incompatibility:
This ntype of incompatibility is resulted due to the formation of undesirable new nproduct when two or more drugs are combined.
Examples nof Chemical incompatibility:
1. nPrecipitation
2. nColour change
3. nEffervescences
4. nDecomposition
Types nof Chemical Incompatibility:
nChemical incompatibility can be intentional i.e. a prescriber knowingly gives nincompatible drugs, or unintentional i.e. prescriber does not know nthat the drugs are incompatible.
There nare two types of chemical incompatibility:
n
n1. Tolerated
Ithis type of incompatibility, chemical reaction can be reduced by mixing the solution idilute forms or by changing the order of mixing.
n
n2. Adjusted
Ithis type of incompatibility, change in the formulation is needed with a ncompound of equal therapeutic value e.g. in the mixture of caffeine citrate and nsodium salicylate, caffeine citrate is replaced with caffeine.
n
n3. Pharmaceutical or physical Incompatibility:
This ntype of incompatibility results by the slow or immediate formation of ndecomposed solutions or nprecipitates, when the drugs are combined in a pharmacy setup or laboratoy.
n
nExamples of Pharmaceutical or physical incompatibility:
1. nInsolubility
2. nLiquefaction
Whethe substances with low melting points such as camphor, menthol and thymol n are mixed together, a liquid mixture i.e. eutectic mixture is formed and nthis process is known as liquefaction.
3. nPrecipitation
Precipitatiocan result when the solvent in which the solute is insoluble is added to the solution. nResins are normally not soluble in water. So, the tinctures of resins may nform precipitate on addition to water.
4. nImmiscibility
nCorrection of pharmaceutical or physical incompatibiliy:
n
nThis can be corrected by using one or more of the following methods:
n
n1. Addition of suspending agents or thickening agents:
Ithe following prescription tragacanth (mucilage or compound powder) is used as na suspending agent.
Phenaceti3g
Caffeine n1g
Orange nSyrup 12ml
Water nupto 90ml
As nPhenacetin is an indiffusible substance.
n
nOn the other hand, tinctures of resins are made soluble in water by the naddition of some thickening agents or with vigorous stirring and shaking.
2. nEmulsification:
Water nand oil are immiscible in each other and they can be made miscible by the naddition of Emulsions. This is known as Emulsification.
3. nChanging the mixing or order of prescription
4. nChanging the form of ingredients i.e. from liquid to solid form or from hydrous nform to anhydrous form:
This nis often helpful in increasing the solubility of a substance e.g.a solution of nephedrine sulfate, an alkaloidal salt, and liquid paraffin is not possible nas alkaloidal salt of ephedrine sulfate is not soluble in liquid nparaffin but anhydrous form of ephedrine is soluble in it. So we use anhydrous nform.
Examples nof Incompatibility:
1. nAcids are incompatible with alkaline salts, carbonates and oxides. They causes nthe precipitation of albumin. So, acids are prescribed alone.
2. nBases and alkaline carbonates must not be prescribed alongwith other drugs in solution. nThey may precipitate metallic and alkaloidal salts.
