PREFORMULATION – POLYMORPHISM

1. PREFORMULATION – POLYMORPHISM Dr. Dinesh M. Biyani, M. Pharm. Ph.D. DBM, DIRPM, Dip TD Associate Professor, SKB College of Pharmacy, Kamptee dineshbiyani10@gmail.com

2. POLYMORPHISM Polymorphism and related phenomena: Polymorphism is defined as “A solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of that compound in solid state” Halebain & McCrone Polymorphism have different physicochemical properties such as m. p., solubility, density etc. so its occurrence has important formulation, biopharmaceutical and chemical process implications.

3. So Preformulation protocol should investigate and characterize these phenomena so that 1.the desired forms can be consistently manufactured 2.the effect of pharmaceutical manipulations are understood E.g. granulation, milling, compression, and 3.the effect of storage conditions on the dosage form can be evaluated and predicted, E.g. crystal growth in suspension, creams, MDIs etc. Enantiotropic – one polymorph can be reversibly change into another one by varying temp. or pressure Monotropic – the change between the two forms is irreversible

4. “Investigations of polymorphism can never be considered to be completely exhaustive in that there is always the possibility that with a specific seeding a heretofore unknown crystal modification may appear…. and…. there is always the possibility of finding a new modification from some unique solvent and condition.” Kuhnert – Brandstatter and Gasser Choice of conditions to screen for polymorphism Crystallization from different solvents at different speeds and temp. Precipitation Concentration or evaporation Crystallization from the melt Grinding and compression Lyophilization Spray drying

5. CRYSTALLINITY AND POLYMORPHISM Characterization of a solid form involves verifying that solid is expected chemical compound Characterizing the internal structure Describing the habit of crystal Crystal habit: - A single internal structure may have different habits depending on the environment for growing crystals Internal structure: - Changes with internal structure alter habit but chemical changes like conversion of salt to free form changes both

6. Amorphous – Many a times solute precipitates out of solution so that the molecules in resulting solid are not ordered in a regular array but in a more or less random arrangement. E.g.. By shock cooling, sudden change in solvent of crystallization, lyophilization. thermodynamic energy solubility/ dissolution rate But this form can be converted to crystalline form due to bulk processing (e.g.. Tabletting) Crystalline – characterized by repetitious spacing of constituent atoms/ molecules in a 3- D array It may contain either stoichiometric(hydrate/solvate) or non stoichiometric (clathrates) amount of crystallization solvent Polymorph: - Different crystalline structure, not isomer Criteria for a compound to exist polymorphism Two polymorph identical in liquid or vapour state Polymorph on melting will give same composition Properties: m.p., solubility, density, hardness, crystal shape, optical properties, electrical properties, vapour pressure, stability changes

7. HABIT Acicular Angular Bladed Crystalline Dendritic Fibrous Flaky/Platy Granular Irregular Nodular Prismatic Spherical Tabular DESCRIPTION Elongated prism, needle like Sharp edged, roughly polyhedral Flattened acicular Geometric shape fully developed in fluid Branched crystalline Regular/ Irregular thread like Plate/ Salt like Equidimensional irregular shape Lacking any symmetry Rounded irregular shape Columnar prism Global shape Rectangular with a pair of parallel faces Crystal Morphology (Habit)

8. Habit of a crystal arises due to the way in which the solutes orientate themselves when growing; therefore, the general shape of a crystal is the result of the way individual faces grow. Crystal morphology/ habit can influence many properties of the compound E.g. Powder flow properties, compaction, stability 1. Tolbutamide B (plate like) cause powder bridging in hopper & capping problems when tableted Form A without problems tableted Flowability of particles increased with increasing shape factor and porosity of a powder bed decreased as the sphericity increased 2. Paracetamol – needle, cube and plate shaped crystals Needle shaped powder had worst compression properties, shows greater capping & lamination Dissolution 3. Aspirin Bioavailability 4. Pentetrazole

9. CRYSTAL CHARACTERISTICS & BIOAVAILABILITY: If Bioavailability is dissolution rate limited If compound is relatively soluble, it is not important E. g. Chloramphenicol palmitate (B) Riboflavin (III) Cortisone acetate (II) Chlortetracyclin HCl (b) CRYSTAL CHARACTERISTICS & STABILITY: For drugs prone to degradation in solid state, physical form is important. Under stress condition, anhydrous crystalline is degraded more rapidly than solvate form Desolvation by excessive heat causes new crystal form which degrade fast So processing variables are very important and the Preformulation scientist should confer stability by converting polymorph E.g. Aztreonam (monobactom antibiotic) – at a condition of high RH (75%,370 C) – a form(needle like having t1/2 of 6 months) undergoes b lactamHOH where b form (spherical) has t1/2 of several years.

10. TABLETTING BEHAVIOUR: Flow and compaction are important, they are related with morphology, tensile strength, and density of powder bed & these can differ for different polymorphs. Morphology crystal habit ( influenced by presence of impurity, concentration, rate of crystallization & hydrodynamics in crystallizer) Compaction can be described as “ Packing of particles by diffusion into Void spaces, elastic and plastic deformation, fracture & cold working and finally, compression of the solid material” by Cole et. al. It is affected by crystal form and habit

11. PHYSICAL STABILITY: Metastable and Stable? Polymorphic changes occur during grinding, granulating, drying and compressing Communition – Digoxin, Spironolactone, Estradiol Compression – Phenyl butazone Granulation can lead to solvate form and drying can cause transformation into anhydrous or amorphous form. Calcium pantothenate is advisable in crystalline form, so while making multivitamin formulations, it is granulated with other vitamins and excipients. Use of amorphous form is not desirable, because polymorphic transformation renders the granulating mass sticky.

12. DETERMINING POLYMORPHISM Melt on slide, observe the solidification process between crossed polar If after spontaneous freezing, a transformation occurs spontaneously or can be induced by seeding or scratching, then it is existing polymorphism Heat on a hot stage & observe for solid-solid transformation, if occurs, polymorphism exists Sublime small amount of sample and attempt to induce transformation between sublimate and original by mixing the two in a drop of saturated solution of one of them if one is seeming to be insoluble & seems to increase (because Metastable is converting to stable), then they are polymorphs if samples are not polymorphs, one may dissolve but other will not grow if two are identical, nothing will occur

13. TECHNIQUES TO IDENTIFY POLYMORPHS Microscopy: Sample observed under cross polarizing filters in polarization microscope Amorphous (super cooled glasses or non crystalline solid organic compound, cubic crystal lattice eg. NaCl), then only single refractive index These compounds do not transmit light & they appear black (isotropic compounds Materials with more than one R.I. are anisotropic, appear bright with brilliant colour(birefringence) These are either uniaxial (2 R.I.), biaxial(3 R.I.) Most drugs are biaxial corresponding to either an orthorhombic, monoclinic or triclinic system Polarizing microscope with hot stage is useful instrument for investigating polymorphism, melting points, transition temp.

14. 2. Thermal Analysis: DSC and DTA measure heat loss or gain resulting from physical/ chemical changes as a function of temperature Endothermic reactions – fusion, boiling, sublimation, vaporization, desolvation, solid solid transition, some chemical degradation. Exothermic reactions – crystallization & some degradation Quantitative measures of these have application in Preformulation E.g. purity, polymorphism solvation, degradation, excipient compatibility For characterizing crystal form - ᅀHf from AUC of DSC for melting endotherm Generally sharp symmetric melting endotherm indicate purity while broad asymmetric suggests impurity TGA measures changes in sample weight as a function of time and temp. (isothermal). Desolvation & decomposition processes are generally monitored by TGA DSC and TGA are micro techniques. Degradation during thermal analysis may provide misleading results, but may be detected by HPLC

15. 3. X – Ray: To establish batch – to – batch reproducibility of crystalline form. Random orientation of a crystal lattice in a powder causes x-ray to scatter in a reproducible pattern of peak intensities at distinct angles relative to incident beam. There is no such pattern in amorphous sample. 4. Dilatometry: Change in volume caused by thermal/ chemical effects 5. Others: IR, Proton Magnetic Resonance, NMR, SEM