Pharmaceutical Incompatibilities

INCOMPATIBILITIES When problems arise during: - Compounding - Dispensing - Administration of pharmaceuticals - Problems develop as a result of: - Using two or more drugs - Use of only one drug such as dosage errors TYPES OF INCOMPATIBILITIES - Physical - Chemical - Therapeutic - Combination of types INCOMPATIBILITIES The ff. is essential from a theoretical as well as practical viewpoint: - Solubility - Chemical reactivity - Drug stability - Therapeutic activity CONSEQUENCES OF INCOMPATIBILITY Patient: - May not receive the full therapeutic effect of the medication - Adverse effect due to the formation of toxic products I. PHYSICAL INCOMPATIBILITY Result of: - Insolubility (most frequent cause), - Liquefaction, or - Physical complexation Cause: - Non-uniform - Unsightly or unpalatable mixtures - Possess the potential danger or nonuniform dosage CLASSIFICATIONS OF PHYSICAL INCOMPATIBILITY A. INCOMPLETE SOLUTION - Two or more substances combined not giving a homogenous product - Due to immiscibility or insolubility

Examples: - Silicones are immiscible with water - Gums are insoluble in alcohol - Resins are insoluble in water - Sometimes: physician may prescribe the wrong or insufficient solvent or vehicle - Use of heat - Usually objectionable (except to make slowly soluble substances dissolve more rapidly) - Danger of forming a clear solution (at high temp.) but will deposit crystals on cooling. Remedy: - Undissolved material (not beneficial or objectionable) - Remove by filtration - For doubtful cases: physician should be advised & approval secured before radical steps are taken Rx Terpin hydrate …………………………….. 3g Simple syrup, q.s. ad…………………….. 120 mL M. Sol. The terpin hydrate (loosens mucus) is insoluble in simple syrup. Remedy: Half of the syrup - replaced by alcohol, or isoalcoholic elixir (40%) may be used as solvent low potency drug suspended with acacia, tragacanth or methocel and dispensed with a shake well label. Rx Phenobarbital …………………………. 250 mg Elixir Phenobarbital, q.s…………… 30 mL M. Sol. Sig. Teaspoonful at bedtime. Excess of Phenobarbital (controls seizures) not soluble in the elixir Remedy: Approximately 10 mL of elixir - replaced with alcohol to give a clear solution requires 40 mg more of Phenobarbital as a solid so as to obtain the Phenobarbital potency prescribed B. PRECIPITATION - A substance in one solvent is soluble but insoluble to another solvent added to the solution

Examples: - Resins - precipitated from alcoholic solutions when water is added - Mucilagenous and albuminous substances & some metallic salts - frequently precipitated from aqueous solution when alcohol is added - Many substances - precipitate from a saturated solution when some other substances are dissolved in the solution - Camphor & volatile oils - “salted out” of aromatic waters when salts or metals are dissolved in the liquid. - Boric acid - precipitated from a solution when tragacanth is dissolved in the liquid. - Colloidal solutions - show precipitation on the addition of electrolytes. Rx Potassium bromide …………………… 8.0 g Camphor water qs ad ……………….. 60 mL M. Ft. sol. Camphor is salted out of the saturated camphor water by the electrolyte, which is better able to compete for the water Remedy: Solution of the bromide in a minimum amount of purified water prior to the addition of the camphor water eliminates the incompatibility. Rx Tr. Benzoin Compound ……………… 5.0 mL Glycerin …………………………………… 15.0 mL Rose Water qs ad …………………….. 100 mL M. Ft. lotion Resins and other components of the tincture – soluble only in high alcoholic vehicles. Remedy: Change in solvent system - avoids precipitation Addition of the tincture with rapid stirring - yields a fine colloidal dispersion No suspending agent is necessary C. SEPARATION OF IMMISCIBLE LIQUIDS - Oils dissolved in alcohol - separate on the addition of water. - Ethyl nitrite spirit with a substantial proportion of potassium citrate - separates & floats as a layer

Rx Chloral hydrate ………………………… 15.00 g Sodium bromide ………………………. 11.25 g Elixir Aromatic, qs ad ……………….. 60.00 mL Mixture of chloral alcoholate, chloral & alcohol is salted out by soluble bromides, etc. Appears as immiscible layer & dangerous if taken as one dose. REMEDY: Clear solutions are formed - above 50% alcohol or below 10% alcohol Incompatibility is solved by adding either water or alcohol. NaBr is insoluble in 50% alcohoL Replace elixir with water & syrup or add sufficient water (about 1 oz) to dilute the Rx below 10% alcohol. Physician should be informed D. LIQUEFACTION OF SOLID INGREDIENTS Mixture of solids sometimes liquefy due to: - Formation of eutectic mixtures - Liberation of water of hydration Rx Aminopyrine …………………… 0.3 g Codeine Sulfate ……………… 15.0 mg Belladonna Extract ………… 10.0 mg Acetylsalicylic acid ………… 0.2 g M. Ft. caps. No. 1 DTD No. 12 Liquefies & becomes green within a few days Liquefaction due to a eutectic mixture formed by aminopyrine & ASA Green color is intensification of the green color of the extract as it becomes wet. REMEDY: Changes avoided - by incorporating one grain of light MgO or MgCO3 in each capsule Diluents - divided between the reacting ingredients, these combined with gentle trituration & the remainder of the ingredients incorporated. Another method of filling – allow the liquefaction to take place & then absorb the liquid on sufficient kaolin or MgCO3 to give a suitable capsule fill Rx is triturated until homogeneous then encapsuled & placed in tightly stoppered containers.

Rx Camphor monobromate …………. gr. ss Menthol …………………………………… gr. ss Chloral hydrate ……………….……… gr. II M. One cap. No. 12 Eutectic mixture formation – will liquefy – dispense separately or add adsorbent before mixing

Result of a potentially dangerous product - Should not be dispensed & the physician be consulted

E. INCORRECT FORM PRESCRIBED Physician may prescribe: - An incorrect form for the most efficient preparation of the Rx Example: - Alkaloid salt to be dissolved in liquid petrolatum - Free alkaloid should be prescribed, soluble in liquid petrolatum & the - Alkaloidal salts insoluble in this solvent.

Drugs react like other organic & inorganic compounds If a high energy system can form a more stable, low energy system. Reactions manifest through: - Formation of precipitate evolution of gas - Addition or elimination of water - Absorption or evolution of heat Formation of complexes or chelated

II. CHEMICAL INCOMPATIBILITIES Occur as a result of: - Chemical interaction among the ingredients of a Rx. Incompatible mixtures: - Should not be dispensed without correction, unless so intended by the physician IMMEDIATE INCOMPATIBILITY Occurs instantaneously upon compounding Readily apparent due to: - Effervescence - Precipitation - Color changes DELAYED INCOMPATIBILITIES Other mixtures: - React on such a slow rate that occurs have been termed. - Occur without appreciable visible change/immediate physical evidence of change - May or may not result in loss of therapeutic activity - Rx is dispensed if used up before about 10% of the therapeutic activity is lost. REMEDY: Use of “Store in a Refrigerator” label - Help decrease the rate of loss of activity - Slows down hydrolysis, redox, or other chemical reactions (occur more rapidly at rm temp) Use of“Shake well” label - When applicable to promote uniform dosage

To generalize: Ingredients with chemically: - Similar active groups are usually compatible while - With different active groups will sometimes react

CLASSIFICATION OF CHEMICAL INCOMPATIBILITIES A. OXIDATION Problem with: Stock solutions, inadequately formulated manufactured products, certain Rx mixture may also oxidize if exposed to: Air Excessive storage Temperatures Light Overdilution Incorrect pH adjustment Presence of catalysts. Undergo auto-oxidation (chain reaction type of oxidation): - Oils & fats, phenolic substances, aldehydes & vitamins - used as antioxidants themselves REMEDY: Controlled by addition of still more reactive inhibitors to: - Provide electrons & - Receive the excess energy possessed by the activated molecules B. REDUCTION Less common in Rxs although: - Silver, mercury, and gold salts may be reduced by light to the metallic form C. RACEMIZATION Conversion of an optically active form to an optically inactive form without changing chemical constitution produces reduced pharmacological activity.

D. PRECIPITATION Two or more pharmaceuticals are combined - Formation of an insoluble substance which precipitates from solution Flocculent precipitates - Develop several days after a stock solution or Rx is prepared - Due to delayed incompatibilities - Evidence of the growth of yeasts, molds or bacteria. - Growth due indirectly to a chemical incompatibility if the preservative system is inactivated by a chemical reaction E. EVOLUTION OF GAS Formed by chem. reaction between ingredients. Example: Effervescence caused by the liberation of CO2 from the: reaction of carbonates & acids in aqueous media, - Decomposition of syrups of paraaminosalicylic acid F. COLOR CHANGES Alterations in color Example Laxative - phenolphthalein is colorless in acid solution but purple in alkaline mixtures G. EXPLOSIVE COMBINATION Oxidizing agents are chemically incompatible with reducing agents (redox reactions) Serious explosions may result from certain combinations H. CEMENTATION All or part of the ingredients of a Rx may set a mass of cement-like hardness. Occurs when compounds from: - Hydrates (ex. Plaster of paris) polymerize, or - Convert to new crystal forms I. SEPARATION OF IMMISCIBLE LIQUIDS Immiscible liquids not soluble in the Rx Ex. Chloral hydrate may separate as a layer of insoluble chloral alcoholate in vehicles containing 10-50% alcohol & large amounts of certain soluble salts

J. GELATINIZATION Solutions form a gel when combined with certain substances rarely encountered Example: - Acacia solutions are gelatinized by ferric salt since acacia possesses carboxyl groups which may be cross-lined by trivalent ferric ions to form polymer chains - Collodion is gelatinized by phenol (related bonding reaction) K. DEVELOPMENT OF HEAT OR COLD Chemical reactions with either liberation or absorption of considerable amounts of heat Chem. reactions taking place spontaneously at rm. temp. do so with evolution of heat - Compounds formed with evolution of heat tend to decompose when the temp. is raised - Compounds requiring heat for their formation are more stable at higher temp. L. HYDROLYTIC CHANGES Many substances hydrolyze in water & the change may be hastened by heat, catalyst, esters, amides, certain metals (Zn, Fe), etc. 1. Ionic hydrolysis - Ionized species + H+ or OH- of H2O → unionized insoluble product - Special type of acid-base reaction (change of pH). - Manifested as precipitate of basic salts or hydrolysis - Ex. ZnCl2 + H2O → ZnOHCl + H+ 2. Molecular hydrolysis - Slower rate than ionic - Reduced therapeutic activity Hydrolysis Reactions (Ionic) Rx Zinc sulfate ………………………… 0.03 g Sodium borate …………………….. 0.12 g Rose water, q.s. ad …………….. 30.00 mL M. Formation of & subsequent hydrolysis of zinc borate results in a precipitate ZnSO4 alone will also hydrolyze gradually to precipitate a basic salt. Use of H3BO3 in place of the Na3BO3 will prevent the Hydrolysis of the Zn salts

Hydrolysis Reactions (Molecular) Rx Sodium salicylate …………………………….. 4.0 g Phenobarbital sodium ……………………… 0.6 g Vitamin B Complex Elixir …………………. 240.0 mL M. Vit. B complex elixir has an acidic pH Alkalinity of the salts causes deterioration of the B vitamins via hydrolysis as well as eventual precipitation of the acids of these sodium salts. Dispensing of the salts separately is suggested Hydrolysis Reactions (Molecular) Rx Penicillin G sodium ………………………………… 1,000,000 U Syrup of Cherry, q.s. ad …………………………… 30 mL M. Ft. Sol. Hydrolysis of the penicillin salt occurs in the acidic medium as well as precipitation of penicillin as the free acid Neutral vehicle could be employed to slow down the rate of hydrolysis M. INVISIBLE CHANGES Chem. changes occur without visible evidence of the reaction Changes that destroy or change the therapeutic effect N. DEVELOPMENT OF POISONOUS SUBSTANCES Chem. reaction between two substances producing products which are more toxic than the original substances Ex. KI + Hg2Cl2 (calomel) in the presence of moisture → Hg+2 (toxic) O. IMPLOSION Weak bottles having thin spots or flaws may break inwardly due to the development of a slight vacuum - Bottles of a syrup were broken by implosion due to removal of oxygen from the air in the bottle by oxidation of syrup P. OTHER TYPES OF CHEMICAL CHANGE Incompatibilities such a polymerization, decomposition, substitution, addition, etc.

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III. THERAPEUTIC INCOMPATIBILITIES OCCUR: - When two drugs are administered together to produce a response which differs in nature or intensity from that which was intended - At the site of the drug action CONSEQUENCES: - Therapeutic effectiveness reduced or delayed (physical or chem. reaction) - Loss of activity (hydrolysis/oxidation) - Delay in the release or absorption of drug (Complexation or combination of drugs with proteins, tannins, surfactants & other large molecules) RESPONSIBLE: - Physician rather than the pharmacist but the pharmacist may inform the physician to eliminate: - Errors in Rx writing/interpretation - Overdose (excessive single dose/too frequent administration) - Contraindicated drugs (steroids/peptic ulcer) - Synergistic/Antagonistic effects - Alteration of Rx order requires permission of prescriber DRUG INTERACTIONS Frequently applied to those situations: - Effects of one drug are altered by the prior or concurrent administration of another - Dietary item influences the activity of a drug (e.g., cheese & monoamine oxidase inhibitors) - A drug causes alterations of laboratory test values - A drug essentially interacts with itself (e.g. by stimulating its own metabolism) Mechanisms of drug interaction: 1. DI at the site of absorption – tetracycline (antacids/dairy products); enteric coated (antacid) 2. DI at the site of distribution – warfarin 3. DI at the site of excretion –probenecid/penicillin 4. Drug biotransformation DRUG INTERACTIONS May either be: - Adverse drug interaction - Beneficial Drug Interaction

I. ADVERSE DRUG INTERACTION Noxious (lethal), unintended & occurs at doses normally used in man for prophylaxis or diagnosis or therapy of disease. Occurs when the action of a prescribed drug is: - Potentiated, inhibited or otherwise modified in the patient by an interactant so that an unfavorable response to the drug is elicited Some have been: - associated with inheritable disorders some of which are related to race TYPES OF ADVERSE DRUG REACTIONS: A. Side effects Troublesome, secondary pharmacological effects & usually not very dangerous Useful in determining when the: - Effective dose is reached - May even be beneficial as with the sedative effects of antihistamine syrups given to children Minimized & desired activity retained by: - Reducing the dosage or using the proper combination of drugs B. Extension Effects Excessive pharmacologic actions normally dose-related Show up in patient given enough drug may develop rapidly or may produce a delayed toxic effect through cumulative/increasing build up. Ex. Cumulative toxic effects which are undesirable Yellowing of teeth in the young child given tetracycline Ataxia after chlorpromazine Hypersensitivity reactions also represent overdose of the exquisitely sensitive individual given a normal size dose or due to: - allergies or other immune reactions (require prior sensitization) CLASSIFICATIONS OF ADR 1. Type A (Augmented) – actions related to the pharmacological activity of the drug a) Extension effects - Predictable, dose related responses arising from an extension of therapeutic effect - Prevention is adjustment of dosage regimen. Ex. Benzodiazepines (anxiety neurosis) – sedation and falls/trauma.

b) Adverse effects - Predictable, dose dependent reactions unrelated to the goal of therapy - Often produced by the same drug-receptor interaction responsible for the therapeutic effect, differing only in the tissue/s or organ/s affected. Ex. Atropine –dryness of the mouth codeine – constipation 2. Type B (Bizarre) - Totally abnormal effects, unrelated from the drug’s known pharmacological actions - Very small doses of the drug may elicit the reaction once allergy or idiosyncrasy is established. Ex. Penicillin hypersensitivity –anaphylaxis; reaction disappears on discontinuation of the drug. 3. Type C (Continuous) - Long term effects usually related to the dose and duration of treatment. Ex. Ethambutol – optic neuropathy 4. Type D (Delayed) - Carcinogenesis (hormonal/gene toxicity) - Adverse effects associated with reproduction (teratogens) 5. Type E (Ending of use/Withdrawal syndromes) - Alcohol-delirium tremens (disorientation and visual hallucinations) - barbiturates – restlessness, mental confusion, convulsions 6. Type F (Failure of efficacy) - Therapeutic failure can sometimes be attributed to a lack of efficacy of drug products. - Examples: - Failure to control infection/ apparent antimicrobial resistance; uncontrolled hypertension - Failure of efficacy of the drug can be the result of imperfect or counterfeit manufacture of the product. CAUSES OF ADR 1. Pharmaceutical causes – altering the quantity of drug available for systemic absorption; influencing release rates Systemic availability of drug influenced by: particle size, nature and quantity of excipients and coating materials

2. Pharmacokinetic causes – the way a drug is handled by the body during ADME may affect humans in as adverse manner; ototoxicity with aminoglycosides when used in patients with renal failure. 3. Pharmacodynamic causes – increased sensitivity of target organs in the body to drugs PREDISPOSING/INFLUENCING FACTORS IN ADR Patient-related factors - Presence of renal, hepatic, and cardiac disease - Age - Previous ADR or drug allergy - Sex - Genetic influence - Miscellaneous ( diet, smoking, alcohol, environmental exposures) Drug-related factors - Pharmaceutical properties - Pharmacokinetic properties - Pharmacodynamic effects II. BENEFICIAL DRUG INTERACTION Desired & intended, when a combination of medications produces: - Improved therapy - Perhaps a greater margin of safety - More appropriate onset or duration of action - Lowered toxicity - Enhanced potency with diminished side effects of drug may be modified by prior or concurrent administration of another drug - Improved therapy is possible by judicious use of combined medication but - Serious adverse effects may result from drug interaction MULTIPLE DRUG THERAPY IS JUSTIFIED IF IT PROVIDES: - Greater efficacy than can be achieved with full doses of single drugs - Greater margin of safety - More satisfactory onset or duration of effect REASONS FOR INCREASED EVIDENCE OF DRUG INTERACTIONS:

- Drug potency - Patients see several physicians - Concurrent use of Rx & non-Rx drugs - Patient’s non-compliance - Drug abuse

CLINICAL FACTORS IN DI - Diagnostic errors - Prescribing errors - Insufficient study of the patient - Contraindicated drugs - Excessive single dose - Excessive daily dose - Additive and synergistic combination - Antagonistic combination - Rx writing errors - Nomenclature error - Dosage form error - Drug Administration and Patient Care -- placebo and psychosomatic factors --unpalatability IV. COMBINATION OF FACTORS More than one error or drug interaction problem may occur in a clinical situation. Cause never determined although: - It is the joint responsibility of the physician & pharmacist to find the cause & eliminate any further similar situations. PHARMACIST: Use his training to investigate the pharmaceutical aspects: - Possible drug instability, physical, chemical, therapeutic incompatibilities while cooperating with the physician in exploring clinical aspects (possible drug interactions, adverse drug reactions, diagnostic, prescribing or administration errors, etc.) - Pertinent physical, chemical, pharmacodynamics, pharmacological & pharmaceutical factors CORRECTION OF INCOMPATIBILITIES - Consult the physician - Use pharmaceutical knowledge - Add an ingredient - Remove an ingredient - Change the vehicle - Change an ingredient - Change the dosage form - Read the literature - Consult the Physician - Method used on the Rx -- discuss the matter with prescriber & co-workers

Ex. of acceptable corrections: Use of: modified mixing order - Dispensing with a “shake well” label - Suspension or emulsification with official agents - Most appropriate form of the drug for the vehicle prescribed, - Other procedures where no therapeutically important change is made in the dosage or ingredients of the formula. Borderline cases (depending on the Rx or Relationship between the pharmacist & physician: - Addition of inert ingredients such as: diluents, stabilizers, buffers, stiffening agents, preservatives & other procedures in which the dose or activity is not altered appreciably Procedure requiring approval of the physician: Addition of materials requiring a charge in the dose Addition of: - Unofficial suspending agents, emulsifiers, chelating agents or other materials which may adversely affect the stability - Omission of troublesome ingredients having little therapeutic activity - Filtering out inactive sediments - Dispensing a troublesome ingredient separately - Changing a brand from that specified - Changing the dosage forms, i.e., substituting capsules for powders, pills, tablet, triturates, etc. and other important changes. USE PHARMACEUTICAL KNOWLEDGE In correcting the problems, the following procedures should be considered first: - Modify the mixing order - Dispense with a “shake well” label - Dispense with a “store in a refrigerator” label - Complete the reaction before packing - Protect from air, light & moisture - Add an Ingredient - Suspending agents - Emulsifying agents - Inert solubilizing or miscibility-increasing ingredients - Diluents - Stiffening or softening agents - Remove an Ingredient - Discard the inactive sediment - Separate the two prescriptions

- Change the Vehicle - Increase the volume of mixture & increase dose - Decrease volume of mixture & decrease dose - Change solvent & use the same dose - Change an Ingredient -- Use the most soluble form -- Use the most stable form - Change the Dosage Form --Use a more suitable dosage form --Use a different brand - Read the literature PREVENTING AND MINIMIZING INCOMPATIBILITIES - Each drug should be mixed thoroughly after it is added to the preparation - Solutions should be administered promptly after they are mixed to minimize the time available for a potential reaction to occur - The number of drugs mixed together in an IV solution should be kept to a minimum - If a Rx calls for unfamiliar drugs or IV fluids, compatibility references should be consulted - Drugs.com – to check for drug incompatibilities EXAMPLES OF INCOMPATIBILITIES INSOLUBILITY Rx Potassium iodide ……………….30.0 g Phenobarbital ……………………… 1.0 g Thiamine HCl Elixir, q.s. ad…… 240.0 mL M. Ft. Sol. - Alcoholic conc. of the elixir is not sufficient to dissolve the Phenobarbital or to maintain it in solution - A suspension might be prepared but because of the potency of the Phenobarbital & the danger involved if the patient did not uniformly disperse this drug before taking a dose, dissolution is preferable - Conc of alcohol required to maintain this amount of Phenobarbital in solution is about 27%. - Knowledge of alcoholic conc of the elixir would permit calculation of the amount of alcohol that must be added the Phenobarbital is dissolved in this alcohol; the thiamine lost be replaced of the elixir and the potassium iodide dissolved in the elixir, and the two solutions are mixed. - Sodium Phenobarbital could not be substituted in this system because the acidity of the elixir will precipitate free Phenobarbital and the alkalinity of the sodium Phenobarbital may cause some hydrolysis of the thiamine

Rx Ephedrine sulfate ………………………………………..0.25 g Menthol ……………………………………………………… 0.02 g Mineral oil, light, q.s. ……………………………… 30.0 mL M. Ft. Sol. - Alkaloidal salt is not oil-soluble - Substitution of an anhydrous ephedrine base will permit preparation of a clear solution Rx Peru Balsam ………………………………….2.0 g Petrolatum, q.s. ………………………… 30.0 mL M. Ft. Oint. - Granular ointment results because the semipolar (phenolic) components of the balsam are not miscible with the completely non-polar base - Compounds possessing the proper balance of polar & non-polar groups, so that they can associate with both the petrolatum & the balsam, will permit the preparation of a smooth product. Castor oil will serve this function. - If balsam is first mixed with about an equal amount of castor oil and this mixture incorporated into the petrolatum, a smooth ointment results. Rx Magnesium carbonate ……………………………….7.5 g Sodium bicarbonate …………………………………. 15.0 g Citric acid …………………………………………………. 15.0 g Purified water, q.s. ad ……………………………… 500.0 mL M. Ft. Sol - Final appearance of this Rx depends on the order of mixing - If NaHCO3 is added to a solution of the citric acid, and the MgCO3 is added last, the solution will be incomplete. - If MgCO3 is added to the solution of citric acid first, soluble Mg citrate will be formed - NaHCO3 will be soluble in this mixture and a clear solution will be obtained. Rx Tr. Benzoin Compound …………………………. 5.0 mL Glycerin ………………………………………………… 15.0 mL Rose water, q.s. ad ……………………………….. 100.0 mL M. Ft. Lotion. - Resins & ether components of the tincture are soluble only in high alcoholic vehicles - Change in solvent system results in an unavoidable precipitate

- Addition of the tincture with rapid stirring yields a fine colloidal dispersion - No suspending agent is necessary PHYSICAL COMPLEXATION Rx Phenol ……………………………………….…. 1.0 g Polyethylene glycol – 400 ……………… 10.0 mL ZnO ……………………………………………….. 15.0 g Purified water, q.s. ad ……………………. 100.0 mL M. Ft. Lotion. - Complexation of the phenol with the ether oxygens of the PEG – 400 will produce an unsatisfactory suspension, as well as inactivate the phenol - Substitution of bentonite magma for PEG will permit preparation of a satisfactory product OXIDATION – REDUCTION Rx Sodium Salicylate ………………………………….. 8.0 g Sodium Bicarbonate ……………………………… 16.0 g Peppermint water, q.s. ad …………………….. 180.0 mL M. Ft. Sol. - Solution darkens on standing - Change attributed to the alkaline catalyzed oxidation of the salicylate to a quinoid form number of substances are useful as antioxidants in retarding the color development and, in this formula, 0.1% sodium bisulfite serves this purpose. ACID – BASE REACTIONS Rx Cocaine HCl ………………………….. 0.3 g Boric acid ….. aa …………………………………………. 1.2 g Sodium borate Purified water, q.s. ad …………. 60.0 mL - Alkalinity imparted to the solution by the sodium borate causes precipitation of the water-insoluble cocaine base. Elimination of the sodium borate prevents this incompatibility. - This reaction is typical of most amine salts in the presence of bases or basic salts

Rx Sodium bicarbonate …. aa …………………………………………………..……….. 4.0 g Bismuth subnitrate Water, q.s. ad …………………………………………. 90.0 mL M. Ft. susp. - Hydrolysis of the bismuth subnitrate yields nitric acid, which reacts with the bicarbonate to yield CO2. - Gas formed would be sufficient to rupture the container completion of the reaction prior to dispensing is not feasible because of the slow rate of acid production from the hydrolysis - A satisfactory remedy is to replace the subnitrate salt with the subcarbonate Rx Sodium sulfathiazole ……………………………. 0.65 g Boric acid sol. 2%, q.s. ad. ………………… 15.00 mL M. Ft. Sol. - Acidity of H3BO3 will cause the formation of free sulfathiazole.the product is for use as ear drops, dispensing of a suspension might be considered - a more suitable procedure is to eliminate the boric acid & dispense a clear solution Rx Sodium salicylate ………………………………. 15.0 g Elixir Lactated Pepsin, q.s. ad…………… 120.0 mL M. - Acidic vehicle results in the formation and precipitation of salicylic acid - A change to a neutral or alkaline vehicle or the addition of sufficient alcohol to dissolve the salicylic acid will correct this incompatibility COMBINATION REACTIONS Rx Butyn sulfate …………………………… 0.65 g Silver nitrate …………………………….. 0.060 g Distilled water, q.s. ad …………….. 30.0 mL M. Ft. Sol. - Silver & sulfate ions will combine to form insoluble silver sulfate - Elimination of one of the compounds is necessary

Rx Benzalkonium chloride …………………………..1 : 5000 Amaranth solution to color …………………. M. Ft. sol. 30 mL - Amaranth (Na salt) is an anionic dye and will combine with cationic antibacterial agent to precipitate as well as inactivate it. - Elimination of the amaranth solution is necessary.