incompatiblities in formulation.pptx.....

Integrated pharmaceutical...

1. UNIT-8: Incompatibilities I n F ormulation 1 BY: FM FANTAHUN M.

2. Contents 2 BY: FM Introduction Types of incompatibilities Physical incompatibilities Chemical incompatibilities Therapeutic incompatibilities Correction of incompatibilities

3. Introduction 3 BY: FM Incompatibility is defined as a result of mixing of two or more antagonistic substances and undesirable product is formed, which may affect the safety, efficacy, appearance and stability of the pharmaceutical product. Incompatibilities may be detected by changes in the physical, chemical and therapeutic qualities of the medicine. Incompatibility arise during compounding, manufacturing, packaging, dispensing, storage or administration.

4. Types of Incompatibilities 4 BY: FM Physical Incompatibilities Chemical Incompatibilities Therapeutic Incompatibilities

5. 1. Physical Incompatibilities 5 BY: FM Physical incompatibilities are those in which the physical properties of the ingredients produce a mixture or preparation that is unacceptable in the appearance or accuracy of dosage , non- uniform , or unpalatable mixtures, which pose the potential danger of non- uniform dosage . form various physical changes in final product. Such as color, odor, taste, viscosity and morphology. usually involve properties such as solubility, melting point, polymorphic forms, freezing point, dielectric constant, etc.

6. Cont. . . 6 BY: FM Physical incompatibilities may be corrected by any of the following methods Change the order of mixing Emulsification Addition of suspending agent Addition, substitution or omission of any ingredient

7. Cont. . . 7 BY: FM Manifestations of physical incompatibility: Insolubility : Insolubility of prescribed agent in vehicle Immiscibility : Immiscibility of two or more liquids Precipitation : occurs due to solvents is insoluble when it is added to solution Liquefaction : Liquefaction of solids mixed in a dry state (called eutexia)

8. Cont. . . 8 BY: FM Insolubility: Inability of material to dissolve in a particular solvent system. The majority of incompatibilities are due to insolubilities of the organic as well as inorganic compounds in particular solvents. Incomplete solution can occur when two or more substances are combined and may not give a homogeneous product because of immiscibility or insolubility.

9. Cont. . . 9 BY: FM Example of prescription containing Ephedrine sulfate 0.25g Menthol 0.02mL Liquid paraffin qs 30mL Make a nasal drop Cause ephedrine sulfate is a salt which is soluble in water but insoluble in organic solvents, liquid paraffin. Solution Anhydrous ephedrine sulfate is soluble in liquid paraffin and hence it can be used to prepare clear solution.

10. Cont. . . 10 BY: FM The following factors affect the solubility of prescribed agent in vehicle and may render it less soluble : Change in pH Milling Surfactant Chemical reaction Complex formation Co- solvent Any change in previous factors may lead to precipitation of drugs and change in their properties.

11. Cont. . . 11 BY: FM Precipitation can occur when a vehicle is added to a substance that is soluble in one solvent and is not soluble in this second vehicle or solvent. An example would be the addition of water to compound benzoin tincture. Tincture of benzoin is a solution of benzoin resin in ethanol.

12. Cont. . . 12 BY: FM Example of prescription containing Tincture benzoin 5g Glycerin Rose water qs 10mL 100mL Compound tincture benzoin lotion Cause Tincture benzoin compound contain resins, change in solvent system results in an unavoidable precipitate. Solution Addition of tincture with rapid stirring yields a fine colloidal dispersion.

13. Cont. . . 13 BY: FM Immiscibility : The inability of two or more substances or liquids to readily dissolve into one another. Immiscibility occurs when a vehicle is added to a solution of something like an oil but the oil is not soluble in the second vehicle. This manifestation appears clearly in emulsion, creams, lotions, some types of ointments. Separation in two phases is noticed in these pharmaceutical dosage forms Example would be the addition of water to peppermint spirit where the peppermint oil may come out of solution.

14. Cont. . . 14 BY: FM Example of prescription containing Castor oil Water 15mL 60mL Make emulsion Cause In this prescription castor oil is immiscible with water due to high interfacial tensions, which is a sign of incompatibility. Solution To overcome this type of incompatibility, emulsification is necessary with the help of emulsifying agent and vigorous shaking.

15. Cont. . . 15 BY: FM The following factors lead to immiscibility: Incomplete mixing Addition of surfactant with: Unsuitable concentration False time of addition Unsuitable for the type of emulsion Presence of microorganisms Some bacteria grow on constituents of mixture Temperature Storage must be in room temperature to prevent separation

16. Cont. . . 16 BY: FM Liquefaction Liquefaction of solids mixed in a dry state. It means that when two solid substances are mixed together, conversion to a liquid state take place. It happens through the following methods: Formation of liquid or soft mass (known as eutectic mixture) : when the solid substance is soluble in another solid substance which lead to decrease of its melting point of the mixture to below room temprature and conversion to a liquid in certain ratios. Exit of crystalline water : By mixing hydrated crystals and dry crystals, crystalline water diffuse to dry crystals.

17. Cont. . . 17 BY: FM The medicaments showing this type of behavior are camphor, menthol, phenol, thymol, chloral hydrate and aspirin. If such conditions take place, compounding such powders becomes difficult since the ultimate mixture turns to liquid.

18. Cont. . . 18 BY: FM Example of prescription containing Menthol Camphor Ammonium chloride Light magnesium carbonate Prepare 100g insufflation Cause 5g 5g 30g 60g In this prescription menthol, camphor and ammonia chloride get liquefied on mixing with each other. Solution To dispense this prescription, menthol camphor and ammonium chloride are triturated together to form liquid. Then, add light magnesium carbonate and mix it thoroughly to make free flowing powder

19. 2. Chemical Incompatibilities 19 BY: FM Chemical incompatibilities are those in which the ingredients interact or decompose to give new compounds; these may or may not produce visible changes. Chemical incompatibilities are reaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form. Some of these incompatibilities are also instabilities . Instability describes degradation, including hydrolysis, oxidation, and covalent chemical reactions that may be slowed but not stopped.

20. Cont. . . 20 BY: FM It should be noted that some incompatibilities are intentional , as in the preparation of a product called White Lotion, and others are not intentional , as in the lowering of the pH of a dissolved sodium or potassium salt of the drug with the precipitation of the free form of the drug. These incompatibilities may be instantaneous (precipitate, color change, effervescence) or delayed (drug stability, precipitate) and occur at such a slow rate that no visible change occurs for a time. These incompatibilities should not be dispensed without correction. Chemical incompatibilities may involve different types of chemical interactions e.g. oxidation, hydrolysis, polymerization, isomerization etc.

21. Cont. . . 21 BY: FM Oxidation is defined as loss of electrons or gain of oxygen. Factors lead to oxidation: Presence of oxygen, Light, Temperature, PH, Pharmaceutical dosage form, Type of solvent used, and Presence of unsaturated bonds. How to identify oxidation in pharmaceutical dosage form? Change of color, odor, viscosity of dosage form

22. Cont. . . 22 BY: FM Protection of drugs from oxidation: Addition of Antioxidants : Vitamin E, vitamin C and inorganic sulfur compounds: thiosulfate and polysulfide Addition of chemicals which form complexes with metals e.g. Benzalkonium chloride Protection from light : Using of dark container Storage in dark places Packaging with substances which absorbed light

23. Cont. . . 23 BY: FM Choice of suitable pharmaceutical dosage forms which reduce the possibility of oxidation process (solid dosage forms are better than solutions) Maintenance of pH by using buffer solution Choice of suitable solvent (rather than water) Storage in low temperature Protection from air by: using good closed containers Replacement of oxygen by nitrogen

24. Cont. . . 24 BY: FM Hydrolysis A chemical reaction in which water is used to break down a compound; this is achieved by breaking a covalent bond in the compound by inserting a water molecule across the bond. Factors induce hydrolysis: Presence of water pH (E.g. Atropine: optimal pH=3.1- 4.5) High temperature (Problem by autoclave E.g. procaine)

25. Cont. . . 25 BY: FM Protection from hydrolysis: Protection from moisture by: Packaging with substances impermeable for moisture Addition of substances that absorb water (CaCO 3 ) Using of solvent rather than water Maintenance of pH by using buffer system Formation of complexes : which protect the drug from the effect of water Reducing of solubility of substance (i.e. Suspension instead of solution)

26. Cont. . . Polymerization In polymerization, small repeating units called monomers are bonded to form a long chain polymer . E.g.: Formaldehyde Paraformaldehyde (Polymer: white precipitate ) To avoid this formaldehyde must be stored in suitable temperature and addition of methanol 15%. Ampicillin in high temperature forms polymers which cause allergy. Factors induce Polymerization: Temperature, Light, Solvent, pH and impurities 26 BY: FM

27. Cont. . . 27 BY: FM Isomerization: It means conversion of drug to its isomer Isomers have: Identical molecular formulas but different arrangement of atoms. E.g. in Geometric isomerization, Cis is more therapeutically active than trans (e.g: Vitamin A) E.g. L- Adrenaline is converted to d- adrenaline by change of pH or temperature. L- Adrenaline is more therapeutically active than d- adrenaline, this is not general for other drugs, d- tubocurarine is more active than l- type.

28. 3. Therapeutic incompatibilities 28 BY: FM Therapeutic incompatibilities are now often referred to as drug interactions . It is the modification of the therapeutic effect of one drug by the concomitant administration of another. A therapeutic incompatibility has been defined as an undesirable interaction between two or more ingredients that leads to: Potentiation of the therapeutic effects of the ingredients. Destruction of the effectiveness of one or more of the ingredients. Occurrence of a toxic manifestation within the patient.

29. Cont. . . 29 BY: FM Mechanisms of therapeutic incompatibility They are divided into two groups : Pharmacokinetics interactions: are those in which one agent alters the absorption, distribution, metabolism and excretion of a second drug with a resultant change in the plasma concentration of the later agent. Pharmacodynamics interactions are related to the pharmacological activity of the interacting drugs e.g. synergism, antagonism, altered cellular transport, effect on the receptor site.

30. Cont. . . 30 BY: FM Different kinds of drug interaction Drug - Drug interaction Drug - Excipient interaction Excipient - Excipient interaction Drug - Food interaction Excipient - Packaging interaction

31. Cont. . . 31 BY: FM Drug- drug interaction Drug- drug interactions occur when a drug interacts, or interferes, with another drug . This can alter the way of one or both of the drugs act in the body, or cause unexpected side effects. This action can be synergistic (when the drug's effect is increased) or antagonistic (when the drug's effect is decreased) or a new effect can be produced.

32. Ont. . . 32 BY: FM Synergism Many drugs shows the synergistic effect, when two drugs are given together the effect of each drug is increased E.g. Aspirin and Paracetamol increase analgesic activity Penicillin and streptomycin increase the antibacterial activity. Example of prescription containing Amphetamine sulphate 20 mg Ephedrine sulphate Simple syrup qs 100 mg 100 ml Make a mixture. Both are sympathomimetic drugs that use additive effects. Hence of individual drugs dose should be reduced to avoid the therapeutic incompatibility.

33. Cont. . . 33 BY: FM Antagonism When two drugs are given together and one drug opposes the pharmacological activity of another drug it is known as antagonism . Example of prescription containing Aspirin Probenecid 0.6g 0.5g When prescribed together their combination produces antagonistic effect on probenecid.

34. Cont. . . 34 BY: FM Drug- excipient Interaction Drug- excipient interaction occurs between the API and excipient . E.g. Certain amine drugs (paracetamol) react with lactose (diluent) in the presence of Magnesium stearate to form brown color compound. This may cause darkening of the tablets and the integrity of the tablet maybe loss.

35. Cont. . . 35 BY: FM Excipient-excipient Interaction This type of interaction occurs between two or more excipients in a drug molecule. E.g. In proper addition of electrolyte such as- Ca++ or Mg++ ion in suspension containing sodium carboxymethyl cellulose (Na CMC) which will cause formation of Calcium/Magnesium CMC. The suspending agent will be destroyed and cannot perform its function.

36. Cont. . . 36 BY: FM Drug- food interaction A drug- food interaction happens when the food affects the ingredients in a medicine. Example- Blood- thinning drugs such as Coumadin® (warfarin) interfere with vitamin K- dependent clotting factors. Eating too much green leafy vegetables, which are high in vitamin K, can decrease the ability of blood- thinners to prevent clotting. Excipient- packaging material interaction In some pharmaceutical formulation excipient and packaging material may interact with each other.

37. Correction of Incompatibilities 37 BY: FM Incompatibilities are easier to prevent than to correct. If one can recognize a potential incompatibility and correct it, then it can save time, materials, and money . One must be cautious to not "imagine" incompatibilities where they may not exist. If one cannot be certain, it may be beneficial to prepare a small quantity of a preparation for observation.

38. Table: Methods and techniques used to correct incompatibility 38 BY: FM

39. Cont. . . 39 BY: FM Typically, physicochemical stability is assessed at the pre- formulation stage of development. A drug substance candidate is treated with acid, base, heat, light, and oxidative conditions to assess its inherent chemical stability. Binary mixtures of the drug substance with individual excipients are also investigated at the pre- formulation stage. These tests are performed to determine the drug substance sensitivity to degrade or reactivity with common pharmaceutical excipients. With an understanding of the stability/reactivity of a drug substance in the preformulation stage, it is possible to formulate the drug product to minimize drug decomposition .

40. 40 BY: FM