Lecture-2 Solid State PDF

University of Gezira Faculty of Pharmacy Depar tment of Pharmaceutics 1975 1978 1994 1995 Wad Medani, Sudan...

University of Gezira Faculty of Pharmacy Depar tment of Pharmaceutics 1975 1978 1994 1995 Wad Medani, Sudan 1984 2000 Physical Pharmacy 2023 2023 Ayman Y. Waddad www.u ofg.edu.sd Assistant Professor of a ym a n wa dda d@u ofg.edu.sd Pharmaceutics h t t p s : //www.resea rch ga te.n et/profile/Aym a n _Wa dda d  DRUG SOLID-STATE PROPERTIES AND DISSOLUTION Dissolution of Solid Dosage Forms 1. Wetting 2. Penetration of medium into dosage form 3. Disintegration 4. Deaggregation of granules/aggregates 5. Dissolution from granules/aggregates and fine particles  Basis for solid phase effects on bioavailability  Solid-phases have different thermodynamic activities  Leads to different solubility values and dissolution rates  If the solid phase is meta-stable either in the dosage form or in the GI media (i.e. hydrates & HCl salts), solution mediated transformations to the stable phase may occur  Such transformations can result in decreased and/or variable dissolution and bioavailability  Relationship between solid phase and dissolution  Solid phase can be categorized into: Crystalline: Polymorphs. Solvate/Hydrate. Amorphous ( super cooled liquid).  Stable phase – hydrate, stable polymorph, salt of strong bases, slowest dissolution rate no conversion during dissolution  Meta-stable phase – anhydrous, meta-stable polymorph, salt form, amorphous Conversion to stable phase may occur during dissolution – leading to a change in dissolution rate Kinetics of conversion to stable phase are complicated - depend on solubility and GI/ formulation contents.  Crystals  Polymorphs e.g. Acetaminophen  Crystal Hydrates/Solvates  Amorphous e.g. Thiamine hydrochoride Te et al. 2003 Crystals Factors affecting 1. Supersaturation of solution. crystal 2. Formation of crystal nuclei. forms 3. Crystal growth round the nuclei. Phase transition and their underlying mechanisms Solution Mediated Mechanism  Polymorphism – the ability of a substance to exist as two or more crystalline phases that have different arrangements or conformations of the molecules.  P o l y m o r p h i c t r a n s i t i o n r e f e r s to t h e i n t e r - c o n v e r s i o n a mo n g p o l y mo r p h i c f o r ms a n d can be categorized into: Monotropic. Enantiotropic. Polymorphic Transition (Free energy-temperature phase diagram) Monotropy Enantiotropy  Polymorphism  Examples Choramphenicol palmitate Sulfamethoxydiazine Mefenamic acid Ritonavir Chloramphenicol Palmitate  Classical example of effect of polymorphism on in vivo performance P la sm a P rofiles Pea k P la sm a Level Sulfamethoxydiazine Form II Form II Form III Form III Mefenamic acid  Free energy difference between polymorphs is ~1/3 that of Chloramphenicol palmitate  20-30% difference in solubility Ritonavir  BCS Class IV compound  Indirect effect on bioavailability  Ritonavir was only bioavailable when given in a solution state  Appearance of form II caused precipitation in marketed capsule and solution formulations  Reformulation was required Ba u er, J. et a l.Pharmaceutical Research (2001), 18(6), 859-866.  Crystal Solvates/hydrates  Hydrates – molecular complexes that incorporate water molecules, usually stoichiometrically, in their crystal lattice  Solvates – molecular complexes that incorporate solvent molecules, usually stoichiometrically, in their crystal lattice  Anhydrates – molecular complexes that incorporate no water molecules, usually stoichiometrically, in their crystal lattice Transitions:Hydrates/Solvates 100 Copper Sulfate 9H O 2 Ouabain 8H 0 2 Penta O 2 % Weight Water Tri Oubain.nH 2H O 2 Mono 0 0 0 4.5 30 47 100 0 100 o Pressure, mm Temperature C Haleblian, J.K., J. Pharm Sci., 64 (1975) 1296-1288 Hydrate Conversion Mechanisms De S m idt , Jan H.; Fok kens, Jasper G.; G rij seels, Hans; Crom m elin, Daan J. A. Journal of Pharmaceutical Sciences (1986), 75(5), 497-501. Hydrates  Carbamazepine  Ampicillin  Theophylline Carbamazepine Crysta lliza tion kin etics of h ydra te ph a se a re fa ster th a n th e diffu sion to th e bu lk Di-h ydra te crysta ls n u clea te a n d grow on th e su rfa ce of a n h ydrou s pa rticles Rodriguez-Hornedo, N; M urphy, D. Journal of Pharm aceut ical S ciences (1999), 88(7), 651-660.  Carbamazepine M urphy, D.; Rodriguez-Cint ron, F.; Langevin, B.; Kelly, R. C.; Rodriguez-Hornedo, N.. International Journal of Pharmaceutics (2002), 246(1-2), 121-134. Ampicillin An h ydra te An h ydra te Brit t ain, Harr y G.; G rant , David J. W. Effect s of polym orphism and solid-st at e solvat ion on solubilit y and dissolut ion rat e. Drugs and t he Pharm aceut ical S ciences (1999), 95(Polym orphism in Pharm aceut ical S olids ), 279-330. Theophylline De S m idt , Jan H.; Fok kens, Jasper G.; G rij seels, Hans; Crom m elin, Daan J. A. Journal of Pharmaceutical Sciences (1986), 75(5), 497-501.  Amorphous  Amorphous – Disordered arrangements of molecules that do not show long range order seen in crystals, however shor t-range intermolecular forces do give rise to shor t- range order.  Amorphous terms Tg, glass transition temperature “ Th e gla ss tem pera ture a s usua lly observed occurs wh en th e experim en ta l tim e sca le becom es com pa ra ble to th e m olecu la r rela xa tion tim e..." On h ea tin g or coolin g th is is th e tem pera tu re wh ere th e sa m ple sh ows a n a bru pt ch a n ge in h ea t ca pa city a n d oth er properties. Tc, crystallization temperature The temperature at w hich the amorphous sample spontaneously crystallizes. Depends on the time-scale of the experiment TK,To Kauzmann temperature Paradoxical temperature w here the super cooled liquid and the crystal have the same entropy. Often thought of as the temperature of zero mobility. Tf, fictive temperature Temperature w here the equilibrium system has the same thermodynamic quantity as the non-equilibrium glass , Relaxation time Describes the rate a system approaches equilibrium d x/ d t = x/  H odge, I.M. J. Non-Crystalline Solids 202 (1996) 164  Amorphous  Why use amorphous? H a n cock, Bru n o C.; P a rks, Mich a el. Pharmaceutical Research Mu llin s, J.D. a n d Ma ck, T.J. J. Amer. Pharm. Assoc. 1960, (2000), 17(4), 397-404. 49, 245-248 Amorphous Example Amorphous Crystalline 10-fold in crea se in in trin sic dissolu tion ra te Im provem en t in solu bility is tra n sien t beca u se con version to crysta llin e La w D., et a l J. Pharm Sci (2001), 90(8), 1015-1025. Screening for Amorphous  High energy phase has improved dissolution  Tools for Evaluating Amorphous Solid Dispersions: Solubility Improvement Amorphous phase should provide the best advantage in terms of improved solubility and dissolution rate over the crystalline phase Physical Stability The re-crystallization of the amorphous should be slow so that the amorphous dispersion can have reasonable shelf-life Amorphous: Solubility Improvement Solubility improvement can be evaluated theoretically from melting point, heat of fusion and change in heat capacity data Bruno C. Hancock and Michael Parks, Pharmaceutical Research, 17 (2000) 397 Role of Excipient: Amorphous Anti-plasticization Plasticization Law et. al, J. Pharm Sci., 2001, 90, 1015 Yoshioka, M. Hancock, B.C. and Zografi, G. J. Pharm Sci., 1995, 84, 983-986 Rita n ovir crysta llizes ra pidly Definitions  Salts – ionic complexes of an active moiety in an ionized state with an appropriate counter ion. Salt formation is used to improve the physicochemical proper ties of a drug. Reasons for choosing a salt  Physical properties Melting point Polymorphism Purity Compressibility, flow, bulk density  Dissolution Improve dissolution for oral immediate release (IR) formulations Decrease dissolution for controlled release (CR) or parenteral depot formulations Effect of Salt Form on Intrinsic Dissolution Rate (IDR)  Crystal lattice energy  Diffusion layer pH Forbes, R. T.; York, P.; Da vidson , J. R. In tern a tion a l J ou rn a l of P h a rm a ceu tics (1995), 126(1,2), 199-208. Dissolution rate vs pH for salt and base M. Pudipeddi et al. S olubilit y and Dissolut ion of Weak Acids, Bases, and S alt s. In Handbook of Pharm aceut ical S alt s: Proper t ies, S elect ion and Use. P H S t ahl and C. G Werm ut h (Eds.) 2002 Complications with salts – cont.  Precipitation of very weak bases from strong acid salts.  Precipitation of insoluble HCl salts in stomach Summary  Solid state proper ties influence absorption via the dissolution rate  Meta stable solid phases maximize the dissolution rate but may conver t to stable phases during the process  Stable phases provide the most reproducible but slowest dissolution behavior  If a meta stable phase is used to improve dissolution, the solution mediated kinetics of transformation to stable phase must be understood Solid-state Characterization Methods Solid-state Characterization Methods IMPACT OF FORMULATION AND PROCESSING ON SOLID-STATE PROPERTIES AND PRODUCT QUALITY Transitions I:Mechanisms  Solid-state occurs without intervening transient liquid or vapor phases influenced by environment and other crystalline properties: defects, particle size, impurities etc. consequence: polymorphic, hydration-dehydration, vitrification-crystallization  Melt if heated above melting point and then cooled influence by relative rates of nucleation, crystal growth and cooling rate consequence: polymorphic, vitrification Transitions II:Mechanisms  Solution occurs when drug is completely or partially dissolved in a liquid and upon subsequent solvent removal consequence: polymorphic, hydration-dehydration, amorphous-crystallization  Solution-mediates occurs when metastable phase is completely or partially dissolved in a liquid consequence: polymorphic, hydration-dehydration, amorphous-crystallization but only from metable to the stable phase Solid Phase and Process/Formulation Design  Influence of solid phase on product quality  Influence of process-induced phase changes on product quality Size reduction Granulation Granulation milling and blending Compression and encapsulation Coating  Anticipating and preventing phase transformations in process development Influence of Solid Phase Choice on Product Quality  Solid phase choice influences: G = - RT ln(activity) Activity G dissolution rate bioavailability density hardness manufacturability appearance etc.  Solid phase transition during processing: Solubility: especially poorly soluble compounds Stability etc.  Influence of Process-Induced Phase Changes on Product Quality  Active Pharmaceutical Ingredient (API) Size reduction Impact mill Fluid energy mill  Granulation Wet granulation (low/high shear mixing, fluid-bed mixing, pelletization) Dry granulation (slugging, roller compaction etc.) Melt granulation Spray (and freeze) drying  Granulation milling and blending  Compression and encapsulation  Coating  API Size Reduction  Often necessary first step Facilitates subsequent processing Enhances performance  Potential phase transformation – shearing/cutting – compacting Mechanical – impacting and Thermal Stress – attrition Solid state/melt transformation? API physical properties Hydrate Metastable phase etc. Wet Granulation  Improves Flowability Cohesiveness Compressibility etc.  Potential phase transformation – amount of liquid used Mechanical and – solubility of the drug Thermal Stress – granulation time Solution/solution – drying time mediated transformation? API physical properties Dry Granulation  Method of choice API has desirable compressibility, flow etc. properties Moisture sensitive API  Potential phase transformation – compacting Mechanical – shearing and – attrition Thermal Stress Solid state/melt transformation? API physical properties Melt Granulation  Method of choice Intentionally generate a metastable phase Solvent-free method particularly when dry granulation is not suitable  Potential phase transformation Mechanical – compacting and – shearing Thermal Stress – attrition – amount of liquid Solid state/melt – granulation time Solution and solvent -mediated transformation? – congealing time API physical properties Spray (or Freeze) Drying  Useful homogeneous porous uniform particles produce metastable phase  Potential phase transformation – amount of liquid Mechanical – solubility and – solvent evaporation rate Thermal Stress Solution/solution mediated transformation? API physical properties Granulation Milling and Blending  Process is less harsh than API milling Transformation risk low  Blending with lubricant does not affect solid phase  Presence of excipients affects detection limit Compression and Encapsulation  Tableting Compression force < 40KN May cause phase transformation Caffeine Sulfabenzamide Maprotiline  Encapsulation Phase transformation seldom encountered Coating  Nonfunctional Coat Aqueous or solvent based Highly efficient air exchange Minimal interaction between core and coating liquid Risk of transformation minimum  Functional Coat Modified release products may contain drug in the coating layer Solution or suspension of the drug may be used Solution or solution-mediated transformation possible Anticipa ting a nd Preventing Pha s e Transformation: Crystal Form  Starting material selection: API Select crystal form that is not sensitive to phase transformations induced by thermal or mechanical stresses Alternate salt with fewer crystal forms may be chosen Excipient if necessary E.g. mannitol has been repor ted to produce process-induce age-hardening  Finished product monitoring: Especially if dissolution and/or stability is sensitive to solid phase changes An t i c i pa t i n g a n d P reven t i n g P h a s e Transformation: Process  Hydrates and processing conditions critical relative humidity and temperature milling and dry granulation conditions wet granulating and drying conditions  Moisture sensitive solid phase dry or melt granulation preferable  Enantiotropes and processing conditions solid-solid transition should be avoided  Compression induce phase transformation may be avoided by choosing capsules over tablets Case Study I: ABT-232  Physicochemical Properties Highly water soluble Three different phases Anhydrous melting temperature 189°C Monohydrate dehydration temperature ~90°C and conver ted to anhydrous phase on dehydration Amorphous glass transition 62°C, readily crystallized Chemically stable and compatible with excipients  Formulation Anhydrous API chosen for development Immediate Release with 0.25 to 1% (w/w) drug loading Wet granulation Advanced Drug Delivery Review 2003  ABT- 2 3 2 F o r m u l a t i o n St a b i l i t y a t 4 0 ° C/75%RH Gradual and unexpected loss in potency over 6 months Strength 0.5 mg 1 mg 2 mg Month Potency Potency Potency RSD (%) RSD (%) RSD (%) s (%) (%) (%) 0 101.6 0.33 102.4 0.30 102.8 0.29 0.5 100.8 0.47 98.6 0.48 101.4 0.35 1 96.6 1.08 97.8 1.02 101.1 0.61 3 92.5 2.56 94.1 2.56 97.5 1.72 6 86.3 4.73 91.3 4.57 93.8 3.12 Advanced Drug Delivery Review 2003 ABT-232 Investigation  Wet and drying granulation Solution mediated transformation Wet granulation: monohydrate formation Solid-solid transformation Drying: dehydrated to amorphous Excipients: inhibited crystallization High amorphous content in the formulation was identified as the cause for poor stability PLM, PXRD, Raman etc.  Direct compression Stable formulations Advanced Drug Delivery Review 2003 Case Study II: Carbamazepine  Physicochemical Properties Poorly water soluble Five different phases Three polymorphic forms Dihydrate Amorphous  Formulation Dose upto 400 mg Poor aqueous solubility Reduced risk of solution-mediated transformation Wet granulation Improve flow and compression Advanced Drug Delivery Review 2003 Carbamazepine: API selection  Polymorphs Form I Anhydrous monoclinic Thermodynamically stable Form II Trigonal monotropically related to Form III Form III Triclinic, enantiotropically related to Form I  Solubility Form I < Form III < Form II Dihydrate is the lease soluble Advanced Drug Delivery Review 2003 Carbamazepine: Processing  Wet granulation Transformation to dihydrate observed with all three forms Form I 2.5% Form II 35% Form III 80% Larger amounts of water was required to granulate Forms II and III  Perfomance Greatest amount of dihydrate in tablets was detected when Form II was used Dissolution was also affected by the form used for processing Advanced Drug Delivery Review 2003 Case Study III: Acetaminophen  Solid phase Three different phases Form I, stable Form II, metastable Form III, metastable  Acetaminophen, Form I is often used as a model compound that exhibits poor compaction behavior  Acetaminophen with improved tableting properties Crystallization Metastable Form II Advanced Drug Delivery Review 2003 Acetaminophen: Compaction  Crystallization Dioxane solvate crystallizes to Form I Milling Crystallization is rapid Fused crystal of Form I High cohesion index suitable for direct compression  Metastable Form II Form II has high cohesion index Heckle analysis: better tableting properties Does not convert to Form I during tableting Form II contains well developed slip plane Plastic deformation along slip planes leads to consolidation Advanced Drug Delivery Review 2003