![• Microcalorimetry: Used to characterize thermodynamic properties of
different molecules.
•
Thermal methods: a}DSC[Differential scanning calorimetry]
b}DTA[Differential thermal analysis]c} TGA [thermal gravimetric
analysis]
This method measures heat loss or gain from physical or chemical
chages occurring in sample which is recorded as a function of
temperature as substance is heated at uniform scale.
Advantage:
• I Thermodynamic parameter can be evaluated.
• II Heat of Transition from one polymorph to the other
Ref:https://www.slideshare.net/MahendraMahi28/polymorphism-142600438](https://image.slidesharecdn.com/presentationfinal-200915084252/85/A-Presentation-on-Polymorphism-17-320.jpg)
A Presentation on Polymorphism
- 1. Presentation on POLYMORPHISM Submitted to: Dr.Mohammad Hossain Shariare Associate Professor Department of Pharmaceutical Sciences North South University Submitted By: Name ID Md. Muhib Islam Sarkar 1821381649 Israt Jahan 1821408649 Afsana Akter 1821414049 Sadia Haque Shoily 1821099649 S.M.M. Sharif Nowaz Antu 1821420049
- 6. ENANTIOTROPY 1.Reversible phase transition 2.Metastable to stable 3.Lower melting point has lower heat of fusion MONOTROPY 1. Irreversible phase transition 2. metastable to stable 3.Higher melting point has higher heat of fusion
- 7. 4.Lower melting form is thermodynamically stable below the transition tempareture and high m.p From is stable above the transition tempareture 4.Higher melting form is always thermodynamically stable form
- 8. Properties of polymorphs Packing properties Thermodynamic properties Kinetic properties Spectroscopic properties Surface properties Mechanical properties
- 9. Stability characteristics of polymorph Depending upon relative stability there are two forms of polymorph- 1)Stable form Less aqueous solibility 2)Meta stable form High aqueous solubility
- 10. STRUCTURAL APPREANCE OF POLYMORPHISM Polymorphs can exist in different crystalline shape.
- 11. STRUCTURAL APPREANCE OF POLYMORPHISM Different crystal forms of polymorphs of a particular substance exhibit significance differences in physical properties and chemical reactivities. Exhibit difference in stabilities.
- 12. STRUCTURAL APPREANCE OF POLYMORPHISM Paracetamol is known to have three polymorphs. Stable Form 1 Monoclinic Meta stable form 2 Unstable form 3 Orthorhombic
- 13. Method to identify polymorphism :Optical crystallography • Use in the identification of polymorphs crystal esist in isotropic and anisotropic form • Isotropic examine the velocity of light is same in all direction. • Anisotropic crystal have 2 or 3 different light velocities or refractive index. • Video recording system and polarizing microscope filted during according to heating and cooling stage for investigating polymorph.
- 14. X ray diffraction method • It provide the most complete information about solid state. • By this method one can identify the unit cell dimension &provide specific differences between crystalline forms of given compound. • In an X-ray diffraction measurement a crystal is mounted on a goniometer and gradually rotated while being bombarded with X-ray producing a diffraction pattern of regularly spaced sports known as reflections. • It is tedious time consuming so it is not used or unsuitable for routine use. • This method is based on the scattering of X-ray by crystals
- 15. Hot stage microscopy: Using this technique fluid phase transformation as a function of temperature is observed. Generally silicon oil hot stage microscopy is used for detection of pseudo polymorphs. NMR technique: In this technique, powder sample must be rotated at a special angle with respect to magnetic field.
- 16. FTIR technique : It has been used to quantify binary mixtures of polymorphs. In identification of polymorphs , only solid samples (as mineral oil mulls & KBr pellets) can be used . • In solutions polymorphs of a compound have identical spectra . • Advantages: - Rapid. • Technique is qualitative & quantitative. • Dilatometry: Measure change in volume caused by thermal or chemical effect.Using dilatometry the melting behaviour of Theobroma Oil was studied .Extremely accurate but tedious , time consuming and not widely used .
- 17. • Microcalorimetry: Used to characterize thermodynamic properties of different molecules. • Thermal methods: a}DSC[Differential scanning calorimetry] b}DTA[Differential thermal analysis]c} TGA [thermal gravimetric analysis] This method measures heat loss or gain from physical or chemical chages occurring in sample which is recorded as a function of temperature as substance is heated at uniform scale. Advantage: • I Thermodynamic parameter can be evaluated. • II Heat of Transition from one polymorph to the other Ref:https://www.slideshare.net/MahendraMahi28/polymorphism-142600438
- 18. Application of polymorphism in pharmaceutical industry To avoid manufacturing problem For improvement of therapeutic activity of drug To prevent loss of raw material For better bioavailability of drug
- 19. Manufacturing Problem The knowledge of solid state properties in an early stage of development helps to avoid manufacturing problems, to fine the tune the performance of drugs and provides space for innovations. E.g.-Famotidine which is an excellent histamine H2 receptor antagonist is also found to exist in two different polymorphic forms- 1.Metastable polymorph B 2.Stable polymorph A
- 20. Suspension In preparation of suspension use of a wrong polymorph of a drug, a phase conversion from the metastable to stable polymorph may occur. This result in crystal growth and caking of suspension. E.g.- cortisone acetate was one of the most difficult polymorphic problems to solve.
- 21. Creams When creams are prepared with the active ingredient suspended in the cream base, use of the wrong polymorph can result in a phase inversion to a more stable phase. As a consequence, crystal growth can occur in the vehicle yielding gritty, cosmetically unacceptable creams or products in which the active ingredient is unevenly distributed.
- 22. Solution Flynn has reported some problem in the formulation of a parenteral solution of a drug. In this instance, determination of the water solubility of the compound indicated the drug to be adequately soluble for the concentration required in the formulation. Stability studies on the formulation quickly turned up the presence of precipitate.
- 23. Suppositories The polymorphic changes of a suppository base could result in a product that undergoes a change in its melting characteristics. If the suppository base is of the type that depends on melting at body temperatures to release the active components of the formulations a relatively small change in its melting point could have severe consequences.
- 24. Polymorphism and Generically Equivalent Dosage Forms If the rate of absorption of the active ingredient in an oral preparation is dissolution-rate dependent, the use of a compound exhibiting polymorphism may lead to good or bad consequences. The successful utilization of a polymorph of significantly greater thermodynamic activity (solubility) than the stable modification may provide, in some instances, therapeutic blood levels from otherwise inactive drugs.
- 25. Polymorphism of several drug Drug Substance Polymorphism Aspect Bioavailability Issues in human body Ritonavir 1.Antiretroviral drug belonging to protease inhibitor class and used to treat HIV-1 infection 2.Exhibits conformational polymorphism Having total 5 forms 2 years after the launch of first ritonavir product, several batches failed dissoulation specifications because the presence of a different polymorphic form having 50% lower intrinsic solubility of reference form Oxytetracycline 1.It is a broad spectrum antibiotic 2.Exist in 2 different forms 1. Oxytetracycline showed differences in patients' blood levels 2. Differences in in vitro dissolution of tablets
- 26. Continue…. Drug Substance Polymorphism Aspect Bioavailability Issues in human body Axitinib 1.It is a tyrosine kinase inhibitor of endothelial growth factor of tumor thus prevents growth of cancer 2.60 solvates and 5 anhydrous forms were discovered 1.The commercial formulation under trade name INLYTA which contains the stable anhydrous form Atrovastatin Calcium 1.Inhibitor of 3-hydroxyl-3- methylglutaryl-coenzyme A reductase 2.Strong ability to lowering blood cholesterol 1.Ustable 2.The hydroxyl acid form is converted to lactone form that is 15 times less soluble than the hydroxyl form 3.After oral administration, the absolute bioavailability of atorvastatin is only 14% Chloramphenicol Palmitate 1.It is a prodrug of chloramphenicol with antibiotic properties 2.Exibits 3 forms: Stable, Metastable, Unstable 1.Metastable form dissolves faster than stable form 2.Low serum levels for the stable polymorph were observed. Ref.:www.semanticscholar.org
- 27. Structure of some drug substances: Ritonavir Oxytetracyclin Axitinib Atrovastatin Calcium Chloramphenicol Palmitate
- 28. Regulatory consideration A sponsor of an Abbreviated New Drug Application (ANDA) must have information in the context of generic product and innovator product equivalency. Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance “sameness”. In case of approval a new drug,US FDA states appropriate analytical procedures. (Ref.:sciencedirect.com)
- 29. Conclusion Polymorphism have such serious consequences for the bioavailability of drugs with low aqueous solubility polymorphic forms of a drug differ in the physicochemical properties To check purity/integrity of the API maintain the potency huge scope for further research Difference in the solubility and melting point Metastable form may lead to preferential choice of a polymorph other than stable form
- 30. References Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs:Roberta Censi, Piera Di Martino https://www.sciencedirect.com/science/article/abs/pii/S0169409X03002 242 Wikipedia https://www.semanticscholar.org/paper/Polymorph-Impact-on-the- Bioavailability-and-of-Censi- Martino/45efb7ee5d2393679561197104856379c075fa29