Category: Entertainment

Presentation Description



Presentation Transcript

slide 1:


slide 2:


slide 3:

3 INTRODUCTION • In the formulation of drug dosage forms stability consideration for the active pharmaceutical ingredients API and the excipients is critical. •This is because degradation process leads to loss of efficacy making the drug in a specific packaging not to remain in the specified chemical physical microbiological therapeutic and toxicological specifications. • Therefore understanding the degradation pathways in order to achieve stability of both the drug substance and drug products is a key quality goal.

slide 4:

4 TYPES OF DEGRADATION PATHWAY • Pharmaceutical products tends to deteriorate on storage even though it is expected to retain acceptable chemical physical and microbiological stability. Barnes 2013 • To get desired effect from any pharmaceutical product is has to be stable throughout its shelf life. • Drug substances used as pharmaceuticals have diverse molecular structures therefore they are susceptible to different kinds of degradation pathways. Yoshioka S. and Stella J. 2002 • Degradation of drugs occur through three principal pathways namely Chemical Degradation Physical Degradation Microbial Degradation.

slide 5:

5 CHEMICAL DEGRADATION PATHWAY Barnes2013 David and Alexander 2008 Yoshioka S. and Stella J. 2002 Guillory and Poust 2002. Hydrolysis/Solvolysis Oxidation Photolysis Polymerization Dehydration Isomerisation Racemization Optical Isomerization Geometrical Isomerization Hydration Decarboxylation Chemical Incompatibilities.

slide 6:

HYDROLYSIS / SOLVOLYSIS • Hydrolysis is one of the most common reactions seen with pharmaceuticals since water is part of many products and moisture is everywhere. • Hydrolysis reactions usually depend on PH and temperature in the presence of either hydronium ion or hydroxide ions as catalyst • The degradation rate depends on the substituents R1 and R2 in that electron- withdrawing groups enhance hydrolysis whereas electron-donating groups inhibit hydrolysis. Substituted benzoates having an electron- withdrawing group such as a nitro group in the para position of the phenyl ring R1 exhibit higher decomposition rates than the unsubstituted benzoate. On the other hand the decomposition rate decreases with increasing electron-donating effect of the alkyl group 6

slide 7:

7 Hydrolysis • The active drug undergoes decomposition with the solvent aqueous and non-aqueous present in which the solvent acts as nuclophiles attacking the electropositive center in the drug molecules • Drugs with the following functional groups: esters • amides lactones or lactams Imides may be susceptible to hydrolysis. • Esters e.g. Aspirin cocaine procaine nitroglycerine methyldopa. • Amides: Acetaminophen chloramphenicol indomethacin and sulfacetamide all produce an amino acid through hydrolysis of their amide bond. • Barbiturates hydantoins and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital phenobarbital amobarbital and metharbital undergo ring-opening hydrolysis.

slide 8:

Hydrolysis / Solvolysis 8

slide 9:

9 OXIDATION • Oxidation reaction is the greatest cause of chemical degradation. • It involves most often increase in the number of carbon to oxygen bonds in a molecule or reduction of C-H bonds. Sometimes molecular oxygen is involved at room temperature. This reaction is known as auto-oxidation. Three primary mechanisms exist for oxidative degradations: Nucleophilic and electrophilic oxidations are typically mediated by peroxides. Electron transfer process via catalysis by transition metal such as Cu ions. 0.0002M Cu 2+ has shown to increase the rate of vitamin C oxidation by a Factor of 10 5 . Autoxidation involves free-radicalinitiatedchain reactions.A singlefree- radical can cause oxidation of many drug molecules. • Some functional groups subject to oxidation are phenols aldehydes alcohols and unsaturated fats and oils. Guillory and Poust 2002

slide 10:

10 Oxidation cont… • Auto oxidation process includes: Initiation: In • + RH "In − H + R • Propagation: R • + O2 "ROO • fast ROO • + RH "ROOH + R • rate-limiting Termination: R • + R • "R − R R • + ROO • "ROOR • In order to reduce degradation by oxidation nitrogen and carbon dioxide are often used to replace the airspace in pharmaceutical dosage forms. Bokser and O’Donnell 2012

slide 11:

11 PHOTODEGRADATION • Degradation of light sensitive drugs or excipients by room or sunlight. • Photodegradation occurs when molecules absorb light wavelength especially 300 – 400 nm. UV light causes more damage than red or orange light and shorter wavelengths cause more damage than longer ones. • Photodecomposition involves oxidation mechanism although others like polymerization or ring opening may occur. Once initiated can progress in the absence of light in a chain reaction. • It occurs during manufacture storage and during the use of the product. radical • In susceptible compounds photodecomposition creates free intermediates which can perpetuate chain reactions.

slide 12:

12 Photodegradation cont… • To avoid photochemical reactions photolabile formulations are packaged in coloured containers. •Yellowish green glass is best protector against UV radiation amber colour gives only a little protection from infrared radiation. •The addition of an antioxidant like sodium thiosulfate or sodium metabisulfite hinders the photodegradation of sulfacetamide. • Nifedipinenicardipinenitroprussidechlorthali done acetazolamide retinol riboflavin furosemide and phenothiazines are very labile to photo- oxidation. •Photochemical reactions are common in steroids.

slide 13:

13 POLYMERISATION • This is the process by which two or more identical molecules combine together to form a much larger and more complex molecule. The reactants are called monomers and the products are called polymers. • Eg .Aminopenicillin such as ampicillin sodium in aqueous solution and also formaldehyde. • Formaldehyde solution may result into a formation of white deposit when kept in cold. • In order to avoid polymerisation on storage glutaraldehyde needs to be formulated at an acidic pH where the process does not occur.

slide 14:

14 ISOMERIZATION • Isomerization is the process of conversion of a drug into itsoptical or geometric isomers. The isomers are often of different therapeutic activity. • There are two types of isomerization Optical isomerism: Divided into Racemization: like epimerization it is a reversible conversion between optical isomers also known as enantiomers. Thalidomide is racemic. The R-thalidomide causes birth defect while the S-thalidomide is active against morning sickness. Eg are Penicillins cephalosporins benzodiazepines. Epimerization: in compounds having more than one asymmetric carbon atom in the molecule. Pilocarpine epimerises by base catalysis. Tetracyclines to epitetracycline and ergortamine manifest epimerization by acid catalysis. Geometric isomerism: Forms CIS and Trans isomers of the compounds. E.g. vitamin A forms the cis –trans isomers.

slide 15:

15 OTHERS • DEHYDRATION: is the elimination of a water molecule from the molecular structures. Found in the degradation of prostaglandin E2 and tetracycline • There is formation of a double bond that participatein electronic resonance with neighbouring functional groups. • DECARBOXLATION: Occurs sometimes in drugs with carboxylic acid groups. It is not a common. It is a chemical process that releases carbon dioxide. β-Keto decarboxylation can occur in some solid antibiotics with a carbonyl group on the β-carbon of a carboxylic acid or a carboxylate anion. Decarboxylations also occur in the following antibiotics: carbenicillin sodium carbenicillin free acid ticarcillin sodium and ticarcillin free acid. • CHEMICAL INCOMPARTIBILITIES: occur between APIs and also between API and excipient.

slide 16:

16 PHYSICAL DEGRADATION Polymorphism Particle size Vaporization Evaporation Temperature Efflorescence Hygroscopy Deliquscence

slide 17:

17 POLYMORPHISM • POLYMORPHS are different crystal forms of the same compound caused by exposure to changes in temperature pressure relative humidity drying granulation milling and compression. • Polymorphs differ in their crystal energy in solubility dissolution rate and melting point. The metastable seeks to revert to the most stable form. Steroids sulphamides and barbiturates are notorious for their propensity to form polymorphs. • Examples of drugs that polymerise include amino- penicillins such as ampicillin sodium in aqueous solution and also formaldehyde.

slide 18:

18 ADSORPTION PARTICLE SIZE • ADSORPTION: Drug-plastic interaction has been a major challenge when drugs are stored in plastics materials. This compromises the preservative content and predisposes the drug to microbial degradation. • Up to 50 of nitroglycerin that was stored in PVC infusion for seven days at room temperature. This phenomenon is due to adsorption. • PARTICLE SIZE affects solubility and dissolution and absorption rate also the flowability of pwder. • Decrease in particle size increases surface area of the drug • Suspension and emulsion are more stable at lower particle size.

slide 19:

19 VAPORIZATION EVAPORATION AND TEMPERATURE •Volatile components such as alcohol ether ketones aldehydes iodine volatile oils camphor and cosolvent of lower molecular weight etc. escape from formulation through vaporization even at room temperature leading to drug loss. • Such product should be placed in well closed containers at proper temperature. Eg. Nitroglycerin chloroform and volatile oil. • Evaporation of water from liquid preparation will cause the drug concentration to change with the possibility of crystallization if the solubility of the drug in the solvent is exceeded. Water loss from emulsion will cause it to crack or suspension to cake. •Increase in temperature degrades thermo-labiles it enhances degradation chemically and physically.

slide 20:

20 EFFLORESCENCE HYGROSCOPY DELIQUESCENCE AND EFFERVESCENCE • Efflorescence is the process where some drugs lose water to the atmosphere resulting in increased concentration of the drug. • Saturated solution becomes supersaturated crystallization. • Hygroscopic:Drugs absorb water from the atmosphere causing physical degradation e.g. glycerol and plant extract. • Deliquescent e.g. Absorbs water from the atmosphere and turns to liquid. CaCl 2 potassium citrate ammonium chloride. • Effervescence powders and tablets will deteriorate if stored in moist atmosphere.

slide 21:

21 MICROBIOLOGICAL DEGRADATION • Micro-organisms are everywhere: air foodwater and humans raw materials and finishedproducts. • Degradation due to micro-organisms can render the product harmful to the patient or have an adverse effect on the product properties • Once opened a product degrades microbiologically shortening the shelf life except there is addition of preservatives. • Injectable need to be used immediately the container is opened.

slide 22:


slide 23:

23 REFERENCES • Barnes A.R 2013. Product stability and stability testing in Aultons Pharmaceutics: The Design and Manufacture of Medicines 4th Edition. Editors: Michael Aulton and Kevin Taylor . eBook ISBN: 9780702062520. Imprint: Churchill Livingstone . P650-662. Published Date: 18th June 2013 • Bokser A.D and O’Donnell P .B 2012: Stability of Pharmaceutical Products in Remington Essentials of Pharmaceutics. Edited by Felton L.A. Published by Pharmaceutical Press 2012. Printed in USA. ISBN 978 0 85711 105 0 • David A and Alexander T. F.2008: Drug stability in Physical Pharmacy.P29-42. Published by the Pharmaceutical Press Grayslake IL 60030-7820 USA © Pharmaceutical Press 2008. ISBN 978 0 85369 725 1 • Eissa M.E and Mahmoud A.M 2015. Development of methods for microbial recovery: Pharmaceutical dosage forms including drugs with antimicrobial properties study iii in European Journal of Pharmaceutical and Medical Research 2015 24 P537-549.. • Guillory K.J and Poust R.I 2002: Chemical Kinetics and drug stability in Modern Pharmaceutics 4 th Edition Revised and expanded. Edited by Banker G.S and Rhodes G.T . Published by Marcel Dekker inc. ISBN: 0- 8247-0674-9. Printed in USA.

slide 24:


authorStream Live Help