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Drug excipient interaction

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Drug excipient interaction

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it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.

it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.

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Drug excipient interaction

  1. 1. 1 Presented by- Diptee Gupta M.Pharm (Pharmaceutics) 1st Semester ( 2019-20) CSJM University Kanpur University Institute of Pharmacy Drug Excipient Interaction
  2. 2. 1. Introduction 2. Drug-excipient interaction 3. Importance of these studies 4. Mechanism of drug-excipient interaction 5. Analytical techniques used to detect drug excipient interaction 2 CONTENT
  3. 3. An excipient is a pharmacologically inactive substance formulated alongside the API of a medicine to impart specific qualities to them. 3 Role of Excipients-  Provide bulk to the formulation  Protect, support or enhance the stability of formulation.  Improve bioavailability of drug INTRODUCTION Pharmaceutical Excipients-
  4. 4.  Drug substances are usually in intimate contact with excipient. Although these are pharmacologically inert, they can undergo chemical and physical interaction with drug substance under favourable condition. These interactions can lead to instability resulting in the formulation of new entities. 4 DRUG EXCIPIENT INTERACTION
  5. 5. 5  To find out how compatible an excipient is with API  Maximizes the stability of a dosage form.  Do not have impact on stability of API  Determine the list of excipient that can be used in final dosage form.  Helps to avoid surprise problem during formulation process  These studies are the part of preformulation study and this study data is essential for IND submission. IMPORATNCE OF THESE STUDIES
  6. 6. 6 MECHANISM OF DRUG EXCIPIENT INTERACTION  They can be classified as- Physical interaction Chemical interaction Biopharmaceutical interaction
  7. 7. These are very common in dosage form and also difficult to detect. These involve change in –  Dosage uniformity, color, odor, dissolution, stability or sedimentation rate etc. These interactions can either be beneficial or detrimental to the product performance. Eg. of some these interactions are as follows – 7 1. PHYSICAL INTERACTION Contd….
  8. 8. Interaction Beneficial effect example Detrimental effect example 1.Complexation Cyclodextrin • Tetracycline • Formulation of chlorpromazine with tween 80 and SLS 2. Adsorption Formulation of Indomethacin (NSAID) using kaolin as adsorbent Formulation of Cetyl Pyridinium chloride tablets using magnesium stearate as a lubricant 3.Solid dispersion Formulation of Piroxicam, Norfloxacin, Nifedipine and Ibuprofen using PEG of different grades Interaction between Povidone and stearic acid in a capsule 8
  9. 9. Chemical interaction involves chemical reaction between drugs and excipients or drugs and impurities/ residues present in the excipients to form different molecules. Chemical interactions are almost detrimental to the product because they produce degradation products. They are as follows- 1.Chemical interactions between drug and excipients- Eg are as follows- • Maillard reaction- eg chlorpheniramine and dextrose interaction 9 2.CHEMICAL INTERACTION Primary amines + reducing sugar Form imine Which finally break into amadori compounds Contd….
  10. 10. • Release of diclofenac sodium from matrix tablet was inhibited by polymer chitosan at low pH, due to formation of ionic complex between diclofenac sodium and ionized cationic polymer • Sodium alginate dissolve in water to form large negatively charged anions, co-formulation in aqueous systems with drugs such as neomycin and polymixin (positively charged) result in precipitation. 10 2. Interaction of drug with excipient residues/ impurities- Excipients are not exquisitely pure. They have some residues which affect the drug action. Impurities found in common excipients- Contd….
  11. 11.  Sterilization by autoclaving of parenteral preparations containing dextrose can cause isomerization of dextrose in fructose and formation of aldehyde which react with primary amino group to cause color change.  Peroxide residues in povidone responsible for the enhanced formation of the N- oxide degradation product of the oestrogen receptor modulator, Raloxifene. 11 Excipient Residue Povidone, Polysorbates Peroxides Magnesium stearate Antioxidants Lactose Aldehydes, reducing sugars Benzyl alcohol Benzaldehyde
  12. 12. These are the interactions which are observed after administration of medicine. These interactions occur in the form of- . 12  The interaction is between the medicine (drug substance and excipients) and the body fluids  The interactions have the tendency to influence the rate of absorption of the drug. Various eg. of these interactions are as follows- 3. BIOPHARMACEUTICAL INTERACTION Contd….
  13. 13. a) Premature breakdown of enteric coat – Enteric coating polymers e.g., cellulose acetate phthalate and hydroxyl propyl cellulose acetate phthalate, dissolve prematurely in the stomach in the presence of antacids or drugs cause increase in the pH of the stomach Cause premature release of API in stomach itself, which results in degradation of drug in stomach. e.g., side effects like gastric bleeding as in the case of NSAIDs. 13
  14. 14. b) Increase in gastrointestinal motility- Many excipients such as sorbitol and xylitol have the tendency to increase gastrointestinal motility, thus reducing the available time for absorption of drugs like Metoprolol. c) Effect on P-glycoprotein efflux transporter- P-glycoprotein thus interferes in the bioavailability of different anticancer and other drug substances. Thus, several excipients e.g., Span 20, Tween 20, Tween 80, Pluronic, Poloxamer etc. are incorporated in the formulations which help in inhibition of P-glycoprotein to enhance availability of the drug into the cell, to produce the desired action. 14
  15. 15. 1. Thermal methods- DSC- Differential Scanning Calorimetry DTA- Differential Thermal Analysis Isothermal micro Calorimetry Hot stage microscopy 2. Spectroscopic techniques- FT-IR Spectroscopy Powder X- ray diffraction Solid state NMR 3. Chromatography - SIC-Self Interactive Chromatography TLC-Thin Layer Chromatography and HPTLC HPLC-High Pressure Liquid Chromatography 4. Accelerated stability study 4. Miscellaneous- Radiolabelled Techniques Fluorescence Spectroscopy 15 ANALYTICAL TECHNIQUES USED TO DETECT DRUG-EXCIPIENT INTERACTION-
  16. 16.  DSC is widely used technique to predict any interaction involving thermal changes. METHOD -The preformulation screening of drug-excipient interaction requires (1 : 1) Drug:excipient ratio, to maximize the likehood of observing an interaction. - Mixture should be examined under N2 to eliminate oxidative and pyrrolytic effects at heating rate ( 2,5 or10 degree C/min) on DSC apparatus. 16 DSC- DIFFERENTIAL SCANNING CALORIMETRY
  17. 17. Interaction detected by DSC - 17 Elimination of endothermic peak Any new peak appeared Change in melting point / peak temperature Change in peak shape (height and width) Change in area of peak or enthalpy
  18. 18.  This technique is useful in the investigation of solid-state interactions and detection of eutectics. In this change in temperature between test sample and reference material is measured under controlled and identical condition. This differential temperature is plotted against time or temperature. Interaction can be identified by comparing DTA curve obtained from the test sample with those of reference material. 18 DTA- DIFFERENTIAL THERMAL ANALYSIS • Thermogram (DTA curve) of a mixture show appearance or disappearance of one or more peaks corresponding to those of the components. If any interaction occur- • The thermogram of mixtures show same patterns corresponding to those of the individual components If no interaction occur-
  19. 19. SIC is useful for proteinous drug and excipients. Principle - For different mobile phases (i.e. different excipients) the injected drug have different interactions (may be repulsive or attractive) with the stationary phase of drug leads to shift in retention time Method -It is a modified type of affinity chromatography. Here, drug is made immobilized as the stationary phase & solution to be tested( excipient solution) acts as mobile phase. Measure retention time and compare with non-retained marker. Eg. INF-Tau(an antiviral drug)- Interactions of it with different types of buffers were studied by SIC. Here, buffer is used to prevent aggregations. 19 SIC-SELF INTERACTIVE CHROMATOGRAPHY
  20. 20. 20 Figure (a) Figure (b) Figure (c)
  21. 21. TLC is generally used as confirmative test of compatibility after performing DSC because if sample undergo negligible thermal changes, it will difficult to detect by thermal method Method- stationary phase consist of powder (silica, alumina, polyamide, cellulose etc.) adhered onto glass, plastic or metal plate. Solution of drug, excipient & drug: excipient mixture are prepared & spotted on the same baseline at the end of plate. The plate is then placed upright in a closed chamber containing the solvent which constitutes the mobile phase. Any change in chromatograph such as appearance of a new spot or a change in Rf values of component is indicative of an interaction. 21 TLC & HPTLC
  22. 22. • Lachman & Lieberman, The Theory and Practice of Industrial Pharmacy • N. Fathima, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel Drug excipient interaction and its importance in dosage form development, Journal of applied Pharmaceutical Science 2011 • Priyanka Patel, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel Drug-Excipient compatibility studies: First step for dosage form development, The Pharma Innovation Journal 2015 • Bapi Gorain, Hira Choudhury, Manisha Pandey, Thiagarajan Madheswaran, Prashant Kesharwani and Rakesh K. Tekade Drug– Excipient Interaction and Incompatibilities 2018 22 REFERENCES
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