Chapter-2
Incompatibilities in Prescription
Syllabus: Incompatibilities in prescriptions- study of various types of incompatibilities-physical, chemical and
therapeutic.
Incompatibility occurs as a result of mixing of two or more antagonistic substances and an undesirable product is formed which may affect the safety, efficacy and appearance of the pharmaceutical preparatio. The interaction of a drug with another drug or of a drug with additives adjuncts; dosage errors etc. come under incompatibility.
Types of Incompatibilities
The incompatibilities are of three types:-
(A) Physical incompatibility
(B) Chemical incompatibility
(C) Therapeutic incompatibility
(A) Physical incompatibility
When two or more than two substances are combined together, a physical change takes place and an unacceptable product is formed. Physical incompatibility is usually due to immiscibility, insolubility, precipitate formation or liquefaction of solid materials. These changes which occur as a result of physical incompatibility are usually visible and can be easily corrected by applying the pharmaceutical skill to obtain a product of uniform dosage, an attractive appearance and having satisfactory therapeutic activity. The physical incompatibilities may be corrected by using any one or more of the following methods:-
(i) Change the order of mixing of ingredients of the prescription
(ii) Emulsification
(iii) Addition of suspending agent
(iv) Change in the form of ingredients
(v) By addition, substitution or omission of therapeutically inactive substance to help in compounding of the prescription.
Example of physical incompatibilites
a. Immiscibility : Oils and water are immiscible with each other.
Example:
Rx
Castor oil 15 ml
Water upto 60 ml
Make an emulsion.
In this prescription castor oil is immiscible with water. To overcome this incompatibility an emulsifying agent is used to make a good emulsion.
b. Insolubility :
Insolubility means the inability of material to dissolve in a particular solvent system. incompatibilities are due to insolubility of the inorganic as well as organic compounds in a particular solvent. The majority of physical
The liquid preparations containing indiffusible solids such as chalk, aromatic chalk powder, acetyl salicylic acid, phenacetin, zinc oxide and calamine etc. a suspending agent may be incorporated, so as to increase the thickness of the preparation. It also helps to maintain uniform distribution of the insoluble substances for sufficient long time after shaking the bottle and facilitating uniform measurement of each dose.
Example:
Rx
Phenacetin 3 g
Caffeine 1g
Orange syrup 12ml
Water upto 90 ml
Make a mixture.
In this prescription phenacetin is an indiffusible substance. Compound powder of tragacanth or mucilage of tragacanth is used as a suspending agent to make a stable suspension.Drugs such as sulphur, antibiotics and certain corticosteroids are insoluble in water and are difficult to wet with water. Wetting agents like saponins and polysorbates are used to distribute the powder in prevented by slowly adding the undiluted tincture with vigorous stirring water.
3. Precipitation
A drug in solution may be precipitated, if ibe solvent in which it is insoluble is added to the solution e.g., resins insoluble in water. When tincture containing resinous matter is adda water, resin agglomerates forming indiffusible precipitates. This can to the diluted suspension or by adding some suitable thickening agent. Gum such as acacia, tragacanth and agar, sugars and many other hydrocolloids are precipitated from their aqueous solutions by alcohol or by electrolytes through dehydration process. The preparation which is made in organic solvent when mixed with preparation made in water, the precipitation will occur. e.g., tincture or liquid extracts when mixed with syrups or some aqueous solutions will result in precipitation. When water is added into the Volatile oils are soluble in alcohol. alcoholic solution of volatile oil, the non-aromatic portion of the oil get precipitated and turbidity appears.
Example: Prepare and dispense 100 ml of the following lotion.
Rx
Tincture benzoin compound 5.0 ml
Glycerin 15ml
Rose water in sufficient
quantity to make 100 ml
Tincture benzoin compound contain resins. The change in solvent system results in an unavoidable precipitate. Addition of tincture with rapid stirring yields a fine colloidal dispersion. So there is no need of any suspending agent.
4. Liquefaction : When certain low melting point solids are mixed together, a liquid or soft mass known as 'eutectic mixture' is produced. This occurs due to the lowering of the melting point of mixture to below room temperature. Many chemicals form hydrates, compounds with water of crystallisation, that are stable at room temperature or normai humidity. hydration under the influence of increasing temperature or decreasing humidity. The medicaments showing this type of behaviour are camphor. menthol, thymol, phenol, chloral hydrate and aspirin. These types of But these compounds will tend to release their water of substances create problems when they are dispensed in powder form. These substances can be dispensed by any one of the following meth- ods:-
(i) Triturate together to form liquid and mix with an absorbent like light kaolin or light magnesium carbonate to produce free flowing powder.
(ii) The individual medicament is powdered separately and mixed with an absorbent and then combined together lightly and filled in suitable containers.
Example:
Rx
Menthol 5g
Camphor 5g
Ammonium chloride 30g
Light magnesium carbonate 60g
Make an insufflation.
In this prescription menthol, camphor and ammonium chloride get liquefied on mixing with each other. To dispense this prescription, menthol, camphor and ammonium chloride are triturated together to form liquid. Add light magnesium carbonate and mix it thoroughly to make free flowing powder.
(B) CHEMICAL INCOMPATIBILITY R Chemical incompatibility may be as a result of chemical interactions between the ingredients of a prescription and a toxic or inactive product may be formed. While dispensing such prescriptions, the precautions should be taken either to prevent the formation of harmful product or to correct them and the prescriber must be informed in this regard. Chemical incompatibilities often occur due to oxidation-reduction, acid base hydrolysis or combination reactions. These reactions may be noticed by precipitation, effervescence, decomposition, colour change or by explosion. The prescription having chemical incompatibility should be dispensed only after its correction by the prescriber. Chemical incompatibilities are of two types:-
(1) Tolerated In tolerated incompatibilities, the chemical interac- tion can be minimised by changing the order of mixing or mixing the solutions in dilute forms but no alteration is made in the formulation.
(2) Adjusted : In adjusted incompatibilities the chemical interaction can be prevented by addition or substitution of one of the reacting
ingredients of a prescription with another of equal therapeutic value. For example, caffeine citrate can be substituted with caffeine in sodium salicylate and caffeine citrate mixture.
The chemical incompatibility may be :
(i) Intentional : when t prescriber knowingly prescribes the incompatible drugs;
(ii) Un-i tional : When the prescriber prescribes the drugs without knowine the there is incompatibility between the prescribed drugs. Precipitate Yielding Interactions
Generally it is observed that reaction between strong solutions pre ceeds at a faster rate and precipitates formed are thick which do no diffuse readily. The light diffusible precipitates are formed when dilute solutions of reacting substances are mixed. stances should be diluted to the maximum extent before mixing them Hence the reacting sub- The precipitates so formed may be diffusible or indiffusible, The method A andB is followed in dispensing the prescription yielding diffusible and indiffusible precipitates respectively.
Method A – The method is followed when diffusible precipitates are formed in very small quantity. Divide the vehicle into two equal portions. Dissolve one of the reacting substances in one of the portion and the other in the other portion. Mix the two portions by slowly adding one portion to the other by rapid stirring.
Method B – The method is followed when indiffusible precipitates are formed in large quantity. Divide the vehicle into two equal portions. Dissolve one of the reacting substances in one portion. Weigh a suitable quantity of compound tragacanth powder (2 g per 100 ml of finished product) and transfer in a mortar and use part of second portion of vehicle to produce a smooth mucilage. Then add other reacting sub- stances. Mix the two portions by slowly adding one portion io the other with rapid stirring. A secondary label "Shake the bottle before use" should be fixed on the container whenever method A or method B is followed in dispensing the prescription.
Examples of Chemieal Incompatibilities and Methods of Their Correction
(1) Alkaloidal Incompatibility
(i) Alkaloidal salts with alkaline substances : Alkaloids are weak bases. They are almost insoluble in water but alkaloidal salts are solubie in water. If these salts are dispensed with alkaline preparations, such as strong solution of ammonium acetate, aromatic spirit of ammonia, solu- tion of ammonia, ammonium bicarbonate, sodium bicarbonate, the free alkaloid may be precipitated. However, they are not always precipitated, because all alkaloids are slightly soluble in water.
Example 2.5 Strychnine hydrochloride solution Aromatic spirit of ammonia 6 ml 4 ml 120 ml upto Make a mixture. Water
Strychnine hydrochloride is an alkaloidal salt whereas aromatic spirit of ammonia is an alkaline substance. When they react together, the strychnine gets precipitated because the quantity of strychnine hydro- chloride prescribed in the prescription is much more than its solubility in water. The aromatic spirit of ammonia contains negligible amount of alcohol which cannot dissolve the strychnine. Hence it gets pre as diffusible precipitates. Hence follow method A for precipitate yield- ing combination.
Example 2.6 Prepare and dispense 100 ml of the following mixture Ammonium bicarbonate 1.5 g 4.5 g 8.33 ml Sodium bicarbonate Tincture Ipecac Chloroform water sufficient quantity to 100 ml Make a mixture.
Tincture ipecac contains an alkaloid emetine. The insolubility of emetine is 1:1000. 1.0 ml of tincture ipecac contains 0.15 g of emetine. Ammonium bicarbonate and sodium bicarbonate are alkaline substances. The prescribed amount of tincture ipecac will not give precipitation in the mixture.Therefore, a simple mixture is formed.
(ii) Alkaloidal salts with soluble iodides :
In cough mixture, potas- sium iodide is generally prescribed as an expectorant along with tincture ipecacuanha (containing emetine). The quantity of emetine present is usually so low that it cannot react with potassium iodide to get precipi- tated as hydroiodide. Similarly, when strychnine is prescribed along with soluble iodides it forms a very insoluble hydroiodide, the precipitates of which are diffus- ible. Hence, follow method A for precipitate yielding interaction.
are separated as diffusible precipitates. So follow method A for precipi. bined with a drug containing tannins, the alkaloids form tannates which
(iii) Alkaloidal salts with tannins :
The alkaloidal salts when com- The tannates of most alkaloids are insoluble in water; hence strong tate yielding interaction. ten or tannic acid solution is commonly used in alkaloidal poisoning
(iv) Alkaloidal salts with salicylates :
When quinine compounds are combined with salicylates, They form indiffusible precipitates of quinin salicylate. Therefore, follow method B for precipitate yielding combina tions. Example 2.7 Quinine hydrochloride Sodium salicylate 0.12 g 4.0 g Water upto 100 ml Make a mixture. Quinine hydrochloride on reaction with sodium salicylate form quj- nine salicylate which get separated as indiffusible precipitates. Therefore, follow method B for precipitate yielding interactions.
Example 2.8 Caffeine citrate 1.0 g 3.0 g Sodium salicylate Water upto 90 ml Make a mixture. Caffeine citrate is a mixture of equal weights of caffeine and citric acid. The citric acid present in caffeine citrate reacts with sodium salicylate to liberate salicylic acid which get precipitated. If caffeine is used instead of caffeine citrate it forms a soluble complex with sodium salicylates. Hence, substitute caffeine citrate with half as much caffeine as that of caffeine citrate to form a clear mixture.
(v) Alkaloidal salts with soluble iodides and bromides :
Alkaloids like strychnine, morphine, codeine etc. form insoluble hydroiodides and hydrobromide with soluble iodides and bromides. These precipitates are insoluble but diffusible, hence method A should be followed while dispensing.
Example 2.9 Potassium iodide Tincture of stramonium 1.5 g 8.5 ml Chloroform water to make 100 ml Tincture stramonium contains solanaceous alkaloid, which form dif- fusible precipitates of hydroiodides with potassium iodide. So follow method A in dispensing this prescription.
(2) Soluble Salicylates Incompatibilities
(i) Soluble salicylates with ferric salt : Ferric salt reacts with sodium salicylate to liberate indiffusible precipitates of ferric salicylate. Therefore, follow method B for precipitate yielding interactions.
Example 2.10 Ferric chloride solution 2 ml Sodium salicylate 3 g Water upto 90 ml Make a mixture. Ferric chloride reacts with sodium salicylate to form ferric salicylate which get separated as indiffusible precipitates. Therefore, follow method B for precipitate yielding interactions. bicarbonate the precipitates of ferric salicylate remain soluble, hence a clear mixture will be formed.
Example 2.11 illustrate the advantage of prescribing sodium bicarbonate along with ferric chloride solution and sodium salicylate. In the presence of sodium
Example 2.11 Ferric chloride solution 2 ml 3 g Sodium salicylate Sodium bicarbonate 8 g 90 ml Water add upto Make a mixture. Dissolve sodium salieylate and sodium bicarbonate in about 70 ml of Add the ferric chloride solution, effervescence is produced. When effervescence has ceased, filter through cotton wool and pass sufficient water through the filtrate to produce 90 ml. water.
(ii) Soluble salicylates with alkali bicarbonates : When sodium salicylate is administered oraliy it reacts with hydrochloric acid present
Chemical incompatibility may be as a result of chemical interactions between the ingredients of a prescription and a toxic or inactive product may be formed.
Chemical incompatibilities are of two types:-
Tolerated : In tolerated incompatibilities, the chemical interaction can be minimised by changing the order of mixing or mixing the solutions in dilute forms but no alteration is made in the formulation.
Adjusted : In adjusted incompatibilities the chemical interaction can be prevented by addition or substitution of one of the reacting ingredients of a prescription with another of equal therapeutic value.
General Methods for Precipitate Yielding Combinations
Generally, it is noticed that reaction between strong solutions proceed at a faster rate and the precipitates formed are thick and do not diffuse readily whereas the reaction between the dilute solutions proceed at a slow rate and the precipitates formed are light and diffuse readily in the solution.
The precipitates so formed may be diffusible or indiffusible. The methods adopted for dispensing such prescriptions in which diffusible or indiffusible precipitates are formed will be described under the heading method A and method B.
Method A This method is used when diffusible precipitates are formed and in those cases where the amount of precipitates formed is very smalI. Divide the vehicle into two equal portions. Dissolve one of the reacting substances in one portion and the other in the other portion. Mix the two portions by slowly adding one portion to the other with rapid stirring.
Method B This method is used when the indiffusible precipitates are formed and they form an appreciable portion of the mixture. Divide the vehicle into two cqual portions. Dissolve one of the reacting substances in one portion. Place the other portion of the vehicle in a mortar, to this incorporate a suitable amount of compound tragacanth powder ( 2 gm per 100 ml of the finished product) with constant trituration until a smooth mucilage is produced, then add and dissolve the other reacting substances. Mix the two portions by slowly adding one portion to the other with rapid stirring.
Whether method A or method B has been used in dispensing the prescription, it is very important to fix a "Shake the bottle." label to the container and ensure that the patient strictly follows and realises the importance of these directions.
Examples of Chemical Incompatibilities and Methods of Their Correction
(1) Alkaloidal Incompatibility
(i) Alkaloidal salts with alkaline substances : Alkaloids are we bases. They are almost insoluble in water but alkaloidal salts are soluk in water. If these salts are dispensed with alkaline preparations, such as strong solution of ammonium acetate, aromatic spirit of ammonia, solu- tion of ammonia, ammonium bicarbonate, sodium bicarbonate, the free alkaloid may be precipitated. However, they are not always precipitated, because all alkaloids are slightly soluble in water.
Alkaloidal salts + alkaline substances =
Alkaloid precipitated (slightly soluble in water)
Hence follow method A for precipitate yield- ing combination.
(ii) Alkaloidal salts with soluble iodides : In cough mixture, potassium iodide is generally prescribed as an expectorant along with tincture ipecacuanha (containing emetine). The quantity of emetine present is usually so low that it cannot react with potassium iodide to get precipitated as hydroiodide. Similarly, when strychnine is prescribed along with soluble iodides it forms a very insoluble hydroiodide, the precipitates of which are diffusible.
Hence, follow method A for precipitate yielding interaction.
(II) Alkaloidal salts with tannins : The alkaloidal salts when combined with a drug containing tannins, the alkaloids form tannates which are separated as diffusible precipitates. So follow method A for precipitate yielding interaction.
The tannates of most alkaloids are insoluble in water; hence tannic acid solution is commonly used in alkaloidal poisoning.
(v) Alkaloidal salts with soluble iodides and bromides : Alkaloids like strychnine, morphine, codeine etc. form insoluble hydroiodides and hydrobromide with soluble iodides and bromides. These precipitates are insoluble but diffusible, hence method A should be followed while dispensing.
(2) Soluble Salicylates Incompatibilities
(i) Soluble salicylates with ferric salt : Ferric salt reacts with sodium salicylate to liberate indiffusible precipitates of ferric salicylate. Therefore, follow method B for precipitate yielding interactions.
(ii) Soluble salicylates with alkali bicarbonates : When sodium salicylate is administered orally it reacts with hydrochloric acid present in the stomach to form salicylic acid which is precipitated and may iritate the gastric mucosa, causing pain in the stomach. Hence, when sodium salicylate is prescribed, it is usually given along with double the quantity of sodium bicarbonate as that of sodium salicylate, to partially neutralise the gastric juice and thus minimising the formation of precipitates of salicylic acid.
(iii) Soluble salicylates and benzoates with acids : Most of the acids and acid syrups (e.g. syrup lemon) decompose sodium salicylate as well as sodium benzoate to form precipitates of salicylic acid and benzoic acid respectively. These precipitates are indiffusible in nature, so follow method B for precipitate yielding interaction.
(iv) Alkaloidal salts with salicylates : When quinine compounds are combined with salicylates, They form indiffusible precipitates of quinine salicylate. Therefore, follow method B for precipitate yielding combinations.
(C) THERAPEUTIC INCOMPATIBILITY
Therapeutic incompatibility may be as a result of prescribing certain drugs to a patient with the intention to produce a specific degree of pharmacological action, but the nature or intensity of the action produced is different from that intended by the prescriber.
This occurs due to the following reasons:-
1. Error in doge;
2. Wrong drug or dosage form;
3. Contra-indicated drugs;
4. Synergistic and antagonistic drugs; and
5. Drug interactions.
Short question & answer :
(i) IN TOLERATED TYPE OF INCOMPATIBILITY
1. Order of mixing is changed
2. Components are omitted or substituted
3. Prescription is referred back to physician
4. Dose is changed
(ii) METHOD A MUST BE FOLLOWED WHEN THE PRECIPITATES
1. Are not formed
2. Are diffusible
3. Are in-diffusible
4. Are filtered
(iii) SODIUM SALICYLATE IS USUALLY ADMINISTERED ORALLY WITH
1. Equal quantity of sodium bicarbonate
2. Double quantity of sodium bicarbonate
3. Half quantity of sodium bicarbonate
4. Administered as such
(iv) HOW DO YOU OVERCOME INCOMPATIBILITY RELATED TO LEMON SYRUP AND SALICYLATES?
1. Follow method B.
2. Replace Lemon syrup with simple syrup and lemon tincture
3. Both I and 2
4. None of the above
(v) HERAPATH REACTION CONSISTS OF AN INTERMEDIATE CALLED AS
1. Hydroiodic acid.
2. Potassium iodide.
3. Quinine Sulphate.
4. Sulphuric acid.
(vi) TYPES OF THERAPEUTIC INCOMPATIBILITIES ARE
1. Error in dosing
2. Contra indicated drugs
3. Drug interactions
4. All of the above
(vii) METHOD B MUST BE FOLLOWED WHEN THE PRECIPITATES
1. Are not formed
2. Are diffusible
3. Are in-diffusible
4. Are filtered
(viii) WHICH METHOD SHOULD BE FOLLOWED WHEN ALKALOIDS REACT WITH SALICYLATES?
1. A
2. B
3. Refer prescription back to physician
4. None of these
(ix) REACTION OF ALKALOIDAL SALTS LIKE STRYCHNINE HCL WITH ALKALINE SUBSTANCES LIKE AROMATIC SPIRIT OF AMMONIA MAYYIELD..
1. Diffusible precipitates
2. In-diffusible precipitates
3. Effervescence
4. Explosion
(x)THE PRECIPITATES FORMED WHEN ALKALOIDAL SALTS REACT WITH TANNINS ARE
1. Diffusible
2. In-diffusible
3. Soluble
4. None of the above
(xi) WHAT HAPPENS WHEN POTASSIUM CHLORATE REACTS WITH OXIDIZABLE SUBSTANCES?
1. Precipitation
2. Effervescence
3. Explosion
4. Color change
(xii) WHEN BARBITURATES LIKE PHENOBARBITONE SODIUM REACT WITH AMMONIUM BROMIDE THE REACTION RESULTS IN ...
1. Separation of Barbitone as diffusible precipitate
2. Separation of Barbitone as In-diffusible precipitate
3. Effervescence
4. Explosion
(xiii) REACTION OF SOLUBLE SALICYLATES WITH FERRIC SALTSYIELDS
1. Diffusible precipitates
2. In-diffusible precipitates ·
3. Effervescence
4. None of the above
(xiv) WHEN ALKALOIDAL SALTS REACT WITH SOLUBLE IODIDES AND BROMIDES..
1. Diffusible precipitates are formed
2. Indiffusible precipitates are formed
3. Effervescence occurs
4. Explosion occurs
(xv) WHILE DEALING WITH INCOMPATIBILITIES THAT INVOLVE EVOLUTION OF CARBON DIOXIDE ONE MUST
1. Carry our reaction in open vessel
2. Use hot water to speed up the reaction
3. Both I and 2
4. None of the above
(xvi) THE COMPOUND FORMED AFTER COMBINATION OF IODINE, HYDROIODIC ACID AND QUININE SULPHATE IS CALLED?
1. Herapathite
2. lodosulphite of quinine
3. Both I and 2
4. None of the above
(xvii) IMMISCIBILITY IS A TYPE OF
1. Chemical Incompatibility
2. Therapeutic Incompatibility
3. Physical Incompatibility
4. All of the above
Lotion of compound tincture of benzoin shows............ type physical incompatibility.
A Precipitation
B Insolubility
C Immiscibility
D Liquefaction
Chalk powder mixture shows which type of incompatibility?
A Therapeutic
B Chemical
C Physical
D Mechanical
Sodium bicarbonate and tartaric acid shows ..........type of chemical incompatibility.
A. Effervescence
B. Complexation
C. Precipitation
D. Hydrolysis
Caffeine citrate and sodium salicylate shows............ type of chemical incompatibility.
A. Effervescence
B. Complexation
C. Precipitation
D. Hydrolysis
..........................is the reaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form.
A. Chemical incompatibility
B. Physical incompatibility
C. Mechanical incompatibility
D. Therapeutic incompatibility
What will happen when you triturate an oxidizing substances like potassium chlorate with an oxidizable substances like sulphur •
A] Explosion
B] Precipitation
C] Liquefaction
D] Eutectic mixture
Tincture of Myrrh precipitates on addition of water, this can be corrected by .
A] Changing solvent
B] Adding an Emulsifying agent
C] Both A and B
D] Only A
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