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ININCOCOMPMPATATIBIBIILILITYTY
Mr. Pankaj Kishori Kusum Ramdas Khuspe
Incompatibility
Definition
Incompatibility refers to interactions
between two or more substances
which lead to changes in ...
Types of Incompatibility
1. Therapeutic incompatibility
2. Physical incompatibility
3. Chemical incompatibility
Vakratunda...
Types of Incompatibility
Vakratunda Foundation, Akluj.
Vakratunda Foundation, Akluj.
Therapeutic Incompatibility
Definition:
It is the modification of the therapeutic
effect of one drug by the prior
concomit...
Mechanisms
Divided into two groups:
1. Pharmacokinetics
 Involve the effect of a drug on another from the
point of view t...
Pharmacokinetic Interactions
1. Altered GIT absorption
2. Displaced protein binding
3. Altered metabolism
4. Altered renal...
1. Altered GIT Absorption
a. Altered pH
b. Altered bacterial flora
c. Formation of drug chelates or
complexes
a. Drug indu...
a. Altered pH
• non-ionized form of a drug is more lipid soluble
and more readily absorbed from GIT than the
ionized form ...
b. Altered Intestinal Bacterial Flora
• E.g.: In 10% 0f patients recieve digoxin:40% or
more of the administered dose is m...
c. Complexation or Chelation
• Chelation (pronounced "key-lation") describes
a particular way that ions and molecules bind...
d. Drug - Induced Mucosal Damage
Vakratunda Foundation, Akluj.
e. Altered Motility
Vakratunda Foundation, Akluj.
2. Displaced Protein Binding
• It depends on the affinity of the drug to plasma
protein. The most likely bound drugs is ca...
3. Altered metabolism
• The effect of one drug on the metabolism of the
other is well documented. The liver is the major
s...
• Therefore, the effect of drugs on the rate
of metabolism of others can involve the
following examples,
1. Enzyme inducti...
4. Altered Renal Execration
• It occur in kidney.
• It may be of following types
A. Inhibition of renal tubular secretion
...
Pharmaco Dynamic Interactions
• It means alteration of the drug action
without change in its serum concentration
by pharma...
Additive effect
• occurs when two or more drugs having the same
effect are combined and the result is the sum of
the indiv...
Potentiation effect
• Describes a particular type of synergistic effect-a
drug interaction in which only one of two drugs
...
Pharmaco Dynamic Interactions
Vakratunda Foundation, Akluj.
Vakratunda Foundation, Akluj.
Physical Incompatibility
• Definition
Interaction between two or more
substances which lead to change in
color, odor, tast...
Manifestations of Physical Incompatibility
• The following list outlines the various ways
incompatibility between or among...
Insolubility
The following factors affect the solubility of
prescribed agent in vehicle and may render it less
soluble:
• ...
Examples of Insolubility
Example :
Rx
Benzalkonium chloride
Sodium lauryl sulfate
• They are not mixed together because
be...
Immiscibility
• This manifestation appears clearly in
emulsion, creams, lotions, some types of
ointments.
• Separation in ...
Immiscibility
• The following factors lead to immiscibility:
– Incomplete mixing
– Addition of surfactant with:
• Unsuitab...
Liquefaction
• It means that when two solid substances are
mixed together, conversion to a liquid state take
place.
• It h...
Vakratunda Foundation, Akluj.
Chemical Incompatibility
Definition
Reaction between two or more substances
which lead to change in chemical
properties of...
Types Of Chemical Changes
1. Oxidation
2. Hydrolysis
3. Polymerization
4. Iso-merization
5. De-carboxylation
6. Absorption...
1.Oxidation
Oxidation is defined as loss of electrons or
gain of oxygen.
• Auto-oxidation:
It is a reaction with oxygen of...
Chemical Groups Which Undergo
Oxidation
• Phenolic compounds :
– Phenylephrine
• Catechol derivatives:
– Adrenaline and no...
Factors lead to oxidation
• Presence of oxygen
• Light:
It can cause photo-chemical reactions: chemical
reaction occur in ...
Factors lead to oxidation
• Pharmaceutical dosage form
Oxidation reaction occur in solutions faster than in solid
dosage f...
Protection of drugs from oxidation
• Addition of Antioxidants and inorganic sulfur
compounds:
Vitamin E, Vitamin C, thio s...
Protection of drugs from oxidation
• Choiceofsuitablepharmaceuticaldosagefor
mswhichreducethepossibilityofoxidationpr
oces...
How To Identify Oxidation
How to identify oxidation in pharmaceutical
dosage form
– For pharmaceutical dosage form :
• Cha...
2.Hydrolysis
Definition:
A chemical reaction in which water is used to
break down a compound; this is achieved by
breaking...
Chemical Groups Which Undergo
Hydrolysis
• Esters:•
– R-C-OR
E.g.: Benzocaine, Procaine
• Amides:•
– R-C-NH-R
E.g.: Chlora...
Factors Induce Hydrolysis
• Presence of water
• pH
– E.g.: Atropine: optimal pH=3.1- 4.5
• High temperature
– Problem by a...
Types of hydrolysis
1. Ionic hydrolysis:
– In which the compound is broken into ions by
water.
– The covalent bond between...
Types of hydrolysis
2. Molecular hydrolysis:
– In which the molecule it self's broken down.
– It is slow process and irrev...
Protection From Hydrolysis
• Protection from moisture by:
– Packaging with substances impermeable for moisture
– Addition ...
3.Polymerization
In polymerization, small repeating units
called monomers are bonded to form a
long chain polymer.
Ex:
For...
Polymerization
Vakratunda Foundation, Akluj.
Factors induce Polymerization
1. Temperature
2. Light
3. Solvent
4. pH
5. Impurities
Vakratunda Foundation, Akluj.
4. Isomerization
–It means conversion of drug to its
isomer
–Isomers have:
• Identical molecular formulas.
• A different a...
Types of Isomerization
1.Optical isomerization
2.Geometric isomerization
Vakratunda Foundation, Akluj.
Optical Isomerization
– Conversion of optical active drug into less
active
E.g.:
• L-Adrenaline is converted to d-adrenali...
Geometric Isomerization
– One type of isomers
– Expressed by cis or trans
•
– Cis:
• Means the groups in the same directio...
5.Decarboxylation
• Decarboxylation is a chemical reaction that
removes a carboxyl group and releases
carbon dioxide (CO2)...
6. Combination
–Take place when the pharmaceutical
dosage form contain substances
with different charges.
E.g.: Surfactant...
Vakratunda Foundation, Akluj.
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Incompatibility

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All Contains of Drug Incompatibility.

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Incompatibility

  1. 1. ININCOCOMPMPATATIBIBIILILITYTY Mr. Pankaj Kishori Kusum Ramdas Khuspe
  2. 2. Incompatibility Definition Incompatibility refers to interactions between two or more substances which lead to changes in chemical, physical, therapeutic properties of the pharmaceutical dosage form. Vakratunda Foundation, Akluj.
  3. 3. Types of Incompatibility 1. Therapeutic incompatibility 2. Physical incompatibility 3. Chemical incompatibility Vakratunda Foundation, Akluj.
  4. 4. Types of Incompatibility Vakratunda Foundation, Akluj.
  5. 5. Vakratunda Foundation, Akluj.
  6. 6. Therapeutic Incompatibility Definition: It is the modification of the therapeutic effect of one drug by the prior concomitant administration of another.  It is also called drug interactions. Vakratunda Foundation, Akluj.
  7. 7. Mechanisms Divided into two groups: 1. Pharmacokinetics  Involve the effect of a drug on another from the point of view that includes absorption, distribution, metabolism and excretion. 2. Pharmacodynamics  Are related to the pharmacological activity of the inter acting drugs. E.g.: synergism, antagonism, altered cellular transport, effect on the receptor site. Vakratunda Foundation, Akluj.
  8. 8. Pharmacokinetic Interactions 1. Altered GIT absorption 2. Displaced protein binding 3. Altered metabolism 4. Altered renal execration Vakratunda Foundation, Akluj.
  9. 9. 1. Altered GIT Absorption a. Altered pH b. Altered bacterial flora c. Formation of drug chelates or complexes a. Drug induced mucosal damage and altered GIT motilityVakratunda Foundation, Akluj.
  10. 10. a. Altered pH • non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. (Therefore, these drugs must be separated by atleast 2hours in the time of administration of both.) Vakratunda Foundation, Akluj.
  11. 11. b. Altered Intestinal Bacterial Flora • E.g.: In 10% 0f patients recieve digoxin:40% or more of the administered dose is metabolized by the intestinal flora. Vakratunda Foundation, Akluj.
  12. 12. c. Complexation or Chelation • Chelation (pronounced "key-lation") describes a particular way that ions and molecules bind metal ions. E.g.: Formation of complex of calcium in milk with tetracycline. Vakratunda Foundation, Akluj.
  13. 13. d. Drug - Induced Mucosal Damage Vakratunda Foundation, Akluj.
  14. 14. e. Altered Motility Vakratunda Foundation, Akluj.
  15. 15. 2. Displaced Protein Binding • It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity. Vakratunda Foundation, Akluj.
  16. 16. 3. Altered metabolism • The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do. E.g.: WBC, skin, lung and GIT. • CYP450 family is the major metabolizing enzyme in phase-I(oxidation process). Vakratunda Foundation, Akluj.
  17. 17. • Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples, 1. Enzyme induction 2. Enzyme inhibition 3. First-pass metabolism Vakratunda Foundation, Akluj.
  18. 18. 4. Altered Renal Execration • It occur in kidney. • It may be of following types A. Inhibition of renal tubular secretion B. Alteration of urine flow and pH Vakratunda Foundation, Akluj.
  19. 19. Pharmaco Dynamic Interactions • It means alteration of the drug action without change in its serum concentration by pharmacokinetic factors. • It include, 1. Additive effect 2. Synergistic effect 3. Potentiation effect 4. Antagonistic effect Vakratunda Foundation, Akluj.
  20. 20. Additive effect • occurs when two or more drugs having the same effect are combined and the result is the sum of the individual effects relative to the doses used. This additive effect may be beneficial or harmful to the patients. Synergistic effect • Occurs when two or more drugs, with or without the same overt effect, are used together to yield a combined effect that has an outcome greater than the sum of the single-drugs active components alone Vakratunda Foundation, Akluj.
  21. 21. Potentiation effect • Describes a particular type of synergistic effect-a drug interaction in which only one of two drugs exerts the action that is made greater by the presence of the second drug. Antagonistic • Reactions have the opposite effect of synergism and result in a combined effect that is less than either active component alone. E.g.: Protamine administered as an antidote to anticoagulant action of heparin Vakratunda Foundation, Akluj.
  22. 22. Pharmaco Dynamic Interactions Vakratunda Foundation, Akluj.
  23. 23. Vakratunda Foundation, Akluj.
  24. 24. Physical Incompatibility • Definition Interaction between two or more substances which lead to change in color, odor, taste, viscosity and morphology. • It is also called pharmaceutical incompatibilities. Vakratunda Foundation, Akluj.
  25. 25. Manifestations of Physical Incompatibility • The following list outlines the various ways incompatibility between or among drug agents may be manifested. 1. Insolubility: Insolubility of prescribed agent in vehicle. 2. Immiscibility: Immiscibility of two or more liquids. 3. Liquefaction: Liquefaction of solids mixed in a dry state (called eutexia). Vakratunda Foundation, Akluj.
  26. 26. Insolubility 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 & change in their properties. Vakratunda Foundation, Akluj.
  27. 27. Examples of Insolubility Example : Rx Benzalkonium chloride Sodium lauryl sulfate • They are not mixed together because benzalkonium chloride is positive charged while sodium lauryl sulfate has negative charge. • By mixing together a precipitate is formed. Vakratunda Foundation, Akluj.
  28. 28. Immiscibility • This manifestation appears clearly in emulsion, creams, lotions, some types of ointments. • Separation in two phases is noticed in these pharmaceutical dosage forms. • Storagemustbeinroomtemperaturetopreve ntseparation Vakratunda Foundation, Akluj.
  29. 29. Immiscibility • 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 E.g.: gelatin Arabic gum • Others produce enzymes which oxidize the surfactant – Temperature Vakratunda Foundation, Akluj.
  30. 30. Liquefaction • 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 mixture: When the solid substance is soluble in another solid substance which lead to decrease of its melting point 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. Vakratunda Foundation, Akluj.
  31. 31. Vakratunda Foundation, Akluj.
  32. 32. Chemical Incompatibility Definition Reaction between two or more substances which lead to change in chemical properties of pharmaceutical dosage form. Vakratunda Foundation, Akluj.
  33. 33. Types Of Chemical Changes 1. Oxidation 2. Hydrolysis 3. Polymerization 4. Iso-merization 5. De-carboxylation 6. AbsorptionofCo2 7. Combination 8. Formation of insoluble complexes Vakratunda Foundation, Akluj.
  34. 34. 1.Oxidation Oxidation is defined as loss of electrons or gain of oxygen. • Auto-oxidation: It is a reaction with oxygen of air which occur spontaneously without other factors. • Pre-oxidants: Are substances catalyze oxidation process i.e. metals, some impurities. Vakratunda Foundation, Akluj.
  35. 35. Chemical Groups Which Undergo Oxidation • Phenolic compounds : – Phenylephrine • Catechol derivatives: – Adrenaline and nor-adrenaline • Some antibiotics: – Tetracyclines • Oils: – Fixed and volatile oils • Vitamins: – lipid and water soluble Vakratunda Foundation, Akluj.
  36. 36. Factors lead to oxidation • Presence of oxygen • Light: It can cause photo-chemical reactions: chemical reaction occur in presence of light. • Temperature: Elevated temperature accelerate oxidation reaction • PH : each drug has its ideal pH for stability. Any change in pH affect drug stability and may accelerate oxidation reaction. Vakratunda Foundation, Akluj.
  37. 37. Factors lead to oxidation • Pharmaceutical dosage form Oxidation reaction occur in solutions faster than in solid dosage forms. • Presence of pre-oxidants as metals & peroxides • Type of solvent used Oxidation reaction occur faster in aqueous solution than others. • Presence of unsaturated bonds : as double and triple bonds (oils) which undergo easier than saturated bonds for oxidation. Vakratunda Foundation, Akluj.
  38. 38. Protection of drugs from oxidation • Addition of Antioxidants and inorganic sulfur compounds: Vitamin E, Vitamin C, thio sulfate and polysulfide • Addition of chemicals which form complexes with metals: EDTA, Benzalkonium chloride • Protection from light: – Using of dark container – Storage in dark places – Packaging with substances which absorbed light – i.e. Oxybenzene Vakratunda Foundation, Akluj.
  39. 39. Protection of drugs from oxidation • Choiceofsuitablepharmaceuticaldosagefor mswhichreducethepossibilityofoxidationpr ocess(soliddosageformsarebetterthansolut ions) • MaintenanceofpHbyusingbuffersolution • choiceofsuitablesolvent(ratherthanwater) • Storageinlowtemperature • protectionfromairby: – usinggoodclosedcontainers – Replacementofoxygenbynitrogen Vakratunda Foundation, Akluj.
  40. 40. How To Identify Oxidation How to identify oxidation in pharmaceutical dosage form – For pharmaceutical dosage form : • Change of color, odor, viscosity of dosage form. – For fixed and volatile oils: • change of color, taste, odor, and viscosity. Vakratunda Foundation, Akluj.
  41. 41. 2.Hydrolysis Definition: 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. Vakratunda Foundation, Akluj.
  42. 42. Chemical Groups Which Undergo Hydrolysis • Esters:• – R-C-OR E.g.: Benzocaine, Procaine • Amides:• – R-C-NH-R E.g.: Chloramphenicol, Sulfonamide • Nitriles: – NO3, N2O, NO2 Vakratunda Foundation, Akluj.
  43. 43. Factors Induce Hydrolysis • Presence of water • pH – E.g.: Atropine: optimal pH=3.1- 4.5 • High temperature – Problem by autoclave Vakratunda Foundation, Akluj.
  44. 44. Types of hydrolysis 1. Ionic hydrolysis: – In which the compound is broken into ions by water. – The covalent bond between ions of compound is broken down. – It is reversible. – E.g.: Codeine phosphate Codeine + Phosphate – This type take place spontaneously – Most affected are weak bases and salts. Vakratunda Foundation, Akluj.
  45. 45. Types of hydrolysis 2. Molecular hydrolysis: – In which the molecule it self's broken down. – It is slow process and irreversible. – It must be avoided. E.g.: Acetyl salicylic acid Salicylic acid +Acetic acid So there is no solutions as dosage forms for Aspirin. H2O Vakratunda Foundation, Akluj.
  46. 46. Protection From Hydrolysis • Protection from moisture by: – Packaging with substances impermeable for moisture – Addition of substances that absorb water (CaCO3) • 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. • Using of surfactants. • Reducing of solubility of substance – .Suspension in stead of solution Vakratunda Foundation, Akluj.
  47. 47. 3.Polymerization In polymerization, small repeating units called monomers are bonded to form a long chain polymer. Ex: Formaldehyde Para formaldehyde • To avoid this formaldehyde must be stored in suitable temperature and addition of methanol 15%. • Ampicillin in high temperature forms polymers which cause allergy. Heat Vakratunda Foundation, Akluj.
  48. 48. Polymerization Vakratunda Foundation, Akluj.
  49. 49. Factors induce Polymerization 1. Temperature 2. Light 3. Solvent 4. pH 5. Impurities Vakratunda Foundation, Akluj.
  50. 50. 4. Isomerization –It means conversion of drug to its isomer –Isomers have: • Identical molecular formulas. • A different arrangement of atoms. Vakratunda Foundation, Akluj.
  51. 51. Types of Isomerization 1.Optical isomerization 2.Geometric isomerization Vakratunda Foundation, Akluj.
  52. 52. Optical Isomerization – Conversion of optical active drug into less active E.g.: • L-Adrenaline is converted to d-adrenaline by change of pH or temperature • L-adrenaline is more therapeutically active than d-adrenaline, a although they have the same physical properties but different arrangement of atoms. • Factors affect optical isomerization: – Temperature – pH – Solvent – Impurities Vakratunda Foundation, Akluj.
  53. 53. Geometric Isomerization – One type of isomers – Expressed by cis or trans • – Cis: • Means the groups in the same direction: – Trans: • Means the groups in opposite direction – Cis is more therapeutically active than trans • E.g.:Vitamine A Vakratunda Foundation, Akluj.
  54. 54. 5.Decarboxylation • Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). NaHCO3 Na+ CO2 – All drugs contain bicarbonate are not sterilized in high temperature Autoclaving Vakratunda Foundation, Akluj.
  55. 55. 6. Combination –Take place when the pharmaceutical dosage form contain substances with different charges. E.g.: Surfactants with positive and negative charges. Vakratunda Foundation, Akluj.
  56. 56. Vakratunda Foundation, Akluj.

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