Solid Form Aspects of Excipients and Their  Influence on Formulation and Process                 Paul Luner, Ph.D.        ...
Overview                                                   QbD• Focus on Solid Dosage Forms        Critical Material Attri...
Lactose Solid Forms                                                                    Aq Solution Equilibrium            ...
Magnesium Stearate          The Impact of Lubricant Level                                                        Amorphous...
Microcrystalline Cellulose                   Alkali/                Mercerization                             Form        ...
Why Worry Now?   BCS BREAKDOWN OF   US TOP 200 IR DRUGS                               EXCIPIENTS USUALLY THE              ...
Form Diversity in Excipients for SDF                                                                    Form Frequency in ...
Impact of Polymorphism and Transformation  Thermodynamics• Mechanical Properties               Polymorph Transition   Poly...
Process Stresses Unit Operation or Process                                        Processing Stresses                    ...
Break Down of Types of Transformation During ProcessingGovindarajan, R.; Suryanarayanan, R. Processing-induced phase trans...
Kinetic Resolution of Phase Composition                                                                                   ...
Excipient Hydration Example: Arginine                                                                                     ...
Mannitol Process Induced Transformation: Good or Bad?                   Crystal Forms of Mannitol                         ...
Calcium Phosphate Dihydrate and AnhydrousCaHPO4 • 2H2O        / RH                                                   CaHP...
Dicalcium Phosphate: Impact of Dehydration                                                                                ...
Secondary Interactions Related to Form Transformation Qualitative Risk Assessment        Secondary Impacts• Excipient mois...
ICH Q6A Guidance:Polymorphism Decision Tree                                        Can      API polymorph                 ...
QbD for Excipients: Solid Form Edition     Focus Area          Control Point       Critical Question     Potential Impacts...
Where do we go from here ? • Industry    •   Know and understand raw materials    •   Choose Wisely    •   Be aware of cha...
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Solid Form Aspects of Excipients and Their Influence on Formulation and Process

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Excipients, which often make up the major proportion of tablet dosage forms are materials that can exist in different solid phases, such as polymorphs, hydrates, amorphous forms or mixed phases. Compendial and manufacturer specifications are typically focused on particulate and chemical attributes. However, variation of excipients at the molecular level can impact their performance characteristics, functionality, and formulation manufacturability. The objective of this presentation is to highlight the diversity of solid form variation in tableting excipients and provide a framework for categorizing their phase compositions. A secondary objective is to relate these categories of phase variation with their propensity for transformation due to manufacturing stresses.

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Solid Form Aspects of Excipients and Their Influence on Formulation and Process

  1. 1. Solid Form Aspects of Excipients and Their Influence on Formulation and Process Paul Luner, Ph.D. Pharmaceutical Development Boehringer Ingelheim Pharmaceuticals Ridgefield, CT August 30, 2012
  2. 2. Overview QbD• Focus on Solid Dosage Forms Critical Material Attributes• Introduce 3 well known examples Functionality• Solid Form Diversity in SDF Excipients Excipient Performance• Phase Transformation and Batch to Batch Variability Processing Stress Supplier Variability• Impact of Solid Form Selection• Impact of Excipient Transformation Global Procurement and• Additional complexities Supply Chain• Recommendations Process Design Space Multi-source suppliers 2
  3. 3. Lactose Solid Forms Aq Solution Equilibrium 35%  / 65%  Aq Lactose Controlled Aq Lactose Suspension Spray Drying Solution Amorphous Crystallize w/ a:b ratio of < 93 °C LH20 > 93 °C input material Form Sol (mg/ml) + LH20 L (~% ?) L @ 20 °C Crystallize H Crystalline Solid Solutions LH20 80 + MeOH/EtOH - H20 5a/3b Amorphous RH 160 ° C %RH Milling L 550  (%RH) 3a/2b /  >50% 4a/1b L L Anhydrous Unstable Stable Hygroscopic Some Mechanical Properties of Lactose Dynamic Brittle Tensile Pure Forms LactoseVromans et al. Int. J. Pharm. 35:29 (1987) 6 D50 Indentation Fracture Strength Type Tablet Tensile Strength (MPa) 5 Hardness Index @ 0.85 SF Amorphous Spray Dried Lactose Anhydrous 4 136 High Moderate High 3 (~70% ) -Lactose Monohydrate 2 Monohydrate 68 High High Low 1 (Crystalline) 310TM Monohydrate 0 104 High High High 10 15 20 25 30 35 SD 316 FF TM Tablet Porosity (%) Carlson and Hancock in Excipient Development for Sebhatu &Alderborn, Pharmaceutical Biotechnology and Drug Delivery Systems, 2006 Eur. J. Pharm. Sci. 1999, 8 (4), 235-242. 3
  4. 4. Magnesium Stearate The Impact of Lubricant Level Amorphous Tablet Hardness Disintegration Time Magnesium Stearate Swaminathan and Kildsig 2001 RH > 70% Ertel and Carstensen 1988 Hydration Magnesium 100% RH Stearate Trihydrate (Dihydrate) Rehydration Dehydration >50 % RH 100 – 105 °C DehydrationStrickland, W. A. J.; Nelson, E.; Busse, L. W.; Higuchi, T. The Anhydrous 100 – 105 °CPhysics of Tablet Compression. IX. Fundamental Aspects of MagnesiumTablet Lubrication. J. Amer. Pharm. 1956, 45 (1), 51-55. Stearate Stearate:Palmitate Material Mechanical Manufacturing And Kinetic Factors Variation Morphology Crystal Form/Hydration Affects Delamination Lubricity Affects Delamination (Blending and Surface Area Composition) Solid State and Impure Material Micromeretics Die Wall Hard to Characterize Sticking Lubrication Flow Aid Specifications Weak Crystal Applied in Kinetic Process 4
  5. 5. Microcrystalline Cellulose Alkali/ Mercerization Form Method For Form II Form I Pair Differentiation I vs. II Raman; PXRD; SS-NMR I I Amorph Ia vs. I IR; SS-NMR > Algae/ >Higher Bacteria Plants/Animals Amorph XPRD; SS-NMR. I/I ~ 0.25 Content Raman, IR Source PXRD Simulated From Crystal Structures Hard or Soft wood Process Particle I Size Crystallinity I5 10 20 30 Moisture Sorption 2-Theta 5
  6. 6. Why Worry Now? BCS BREAKDOWN OF US TOP 200 IR DRUGS EXCIPIENTS USUALLY THE MAJOR COMPONENTS OF SDFs! Unclassified V SI Require BC BCS I 30-40% Formulation BCS II Enablement More Reliance on Excipients + Process to Achieve Performance BCS III Function Excipient Formation Form ???  Proceesing/ DF Behavior Environment DP /Storage Process 6
  7. 7. Form Diversity in Excipients for SDF Form Frequency in SDF Excipients Number of Excipients 50Solid Dosage Form Excipients (n=75) N=75 40 Amorphous/Crystalline Distribution 30 29.3 20 Occuring Only as 10 Amorphous 0 One Two Three Four Five 61.3 Number of Solid Forms (including amorphous) 9.3 Occuring Only as Crystalline Excipients By Category Other Diluents ExcipientsThat Can Lubricants Be Either Binders 0 10 20 30 40 50 % of Excipients in Category with > 1 Solid Form 7
  8. 8. Impact of Polymorphism and Transformation Thermodynamics• Mechanical Properties Polymorph Transition Polymorph Transition • Hardness • Tensile Strength • Compactibility, Tabletability Liquid• Surface Morphology /Chemistry • Surface Energy • Habit• Thermodynamics • MP Amorphous-Crystalline • Heat Capacity Transition Hydrate Formation • Free Energy • Vapor Pressure • Solubility• Hygroscopicity• Kinetics and Chemical Reactivity • Dissolution • Stability 8
  9. 9. Process Stresses Unit Operation or Process Processing Stresses  Thermal* Pressure Mechanical Liquid Vapor Impact Exposure Exposure Crystallization/Precipitation    Milling     Granulation (Fluid Bed= )     Compression (Tableting;   Roller Compaction) Drying   Powder Mixing/Blending   Tablet Coating    Handling/Transport    Storage    Spray Drying    Hot Melt Extrusion  *Thermal Stress defined as potential to exceed recognized suitable long-term storage condition [York 1983. Int. J. Pharm. 14:1-28]
  10. 10. Break Down of Types of Transformation During ProcessingGovindarajan, R.; Suryanarayanan, R. Processing-induced phase transformations and their implications onpharmaceutical product quality. In Polymorphism; Hilfiker, R., Ed., 2006; 333-364..
  11. 11. Kinetic Resolution of Phase Composition Subsequent Wet Massing Phase Drying Phase Storage tGranulation > Amorph ous tSupersaturation tDrying  tEMC Transient Meta- Stable Hydrate stable Form I Form Meta Stable tDrying < Stable Form I Dissolution Form II tConversion II --> I tNucleation/Growth > tDrying > Stable tGranulation tConversion II --> I Form I Meta Stable Stable Stable Dissolution Form I Form I Form II Hydrate Exceed Dehydration tDrying  tEMC Threshold Iso- Hydrate morphic Desolvate Anhydrate Form Adapted from Morris et al. Adv. Drug Del. Rev. 48 (2001):91-114
  12. 12. Excipient Hydration Example: Arginine Arginine Moisture Sorption Isotherm @ 40 OC 25 20 % Weight Change 15 10 (@ 25 C) Prototype Tablets Scale Up Batch 5 Adsorption Desorption 1 day @ 25 °C/60% RH 0 white speckles/ 0 10 20 30 40 50 60 70 80 90 100 dimples % Relative Humidity PXRD Comparison Anhydrate: P 21 Dihydrate: P 21 21 21 a = 9.75, b = 16.02, c = 5.58 a = 5.64, b = 11.85, c = 15.68 V = 863.8 V = 1047.6 "Pimples" Anhydrate Dihydrate 5 10 15 20 25 30 RIET_1_publ ARGIND11 2-Theta Data courtesy of D. Chen, BIPI 12
  13. 13. Mannitol Process Induced Transformation: Good or Bad? Crystal Forms of Mannitol -form -form Thermo Stability ENATIO 97% RH or Water   -form -form Compressibility: >> 97% RH or Water Compactibility:  > = No transformation under mechanical stress Crystalline Mannitol Formulations Direct Compression Wet Granulation • -form undergoes water mediated transformation   • 6X increase in Surface Area • Particle Size Reduction   • Change in Hygroscopicity • Increase in tabletability Yoshinari, T.; Forbes, R. T.; York, P.; Kawashima, Y. Int. J. Pharm. 2003, 258 (1-2), 121. 13
  14. 14. Calcium Phosphate Dihydrate and AnhydrousCaHPO4 • 2H2O  / RH CaHPO4 60 C Isothermal Dehydration DCPD DCPA as a Function of %RH - H2 O H2O (liquid) DCPD is ~ 21% Water by Wt. DCPD Tabletability Tensile Strength @ 32% RH Storage DCPD Hygroscopicity DCPA DCPA Compression Pressure Lot Variation in DCPD Dehydration Kinetics Kaushal, A. M.; Vangala, V. R.; Suryanarayanan, R. J. Pharm. Sci., 100 (4), 1456 (2011). 14
  15. 15. Dicalcium Phosphate: Impact of Dehydration DPArora, K. K.; Tayade, N. G.; Suryanarayanan, R. Molecular Pharmaceutics 2011, 8 (3), 982-989. Manufac. Process Variation Temp/RH Supplier Stress Excipient Solid 40 °C; Closed System Form in CBZ-NMA DF Cocrystal DCPD  CBZ Grade/ Phase Particle Purity Size - H2O • Hydrolysis/Chemical Instability • API hydration/Phase transform • Disintegrant Deactivation • Tablet Hardening • Tg lowering of Amorphous Dispersions 15
  16. 16. Secondary Interactions Related to Form Transformation Qualitative Risk Assessment Secondary Impacts• Excipient moisture uptake ability can Excipient Transformation affect API solid form transformation Risk Assessment in processing # of Potential Solid Forms• Different Forms or Form composition of the excipient affecting moisture => tabletting• Differences in Excipient Form solubility/dissolution rate may affect API dissolution rate• Form or presence of form impurities may impact potential for Eutectic Formation Dosage Form Processing Complexity and Transformational Impact 16• Physical stability of DF in the presence of moisture may be altered
  17. 17. ICH Q6A Guidance:Polymorphism Decision Tree Can API polymorph Polymorphs be No No further action screen formed ? Yes Characterize What Forms Exist ? Forms (Characterization) Does Drug Product Establish 1 performance testing provide Yes acceptance criteria adequate control if polymorph for the relevant content changes performance tests No Do the forms have No further Test or Control of Polymorph No acceptance different properties ? Monitor Polymorph criterion for DS form during stability of DP in DP Yes No No need to set Is drug product safety, Does a change occur acceptance criteria performance or efficacy which could affect safety No for form change in affected ? or efficacy ? DP Single Form Yes Will Crystal Form Yes Or Mixture ? be affected by DP Set Criteria for Polymorph content Manufacture ? Establish acceptance criteria in DS consistent with 2 Safety and Efficacy 3
  18. 18. QbD for Excipients: Solid Form Edition Focus Area Control Point Critical Question Potential ImpactsForm Diversity Selection of What is the right Physical Chemical Excipient Solid Form form for the API and Properties; Process? TransformationInput Form Control Variation in Solid Will material Extent of Form of the variation affect Transformation in excipient based on processing or process; source , grade or product quality ? hygroscopicity/ supplier moisture balanceOutput Form Control Process and its Does process impact Change in variation impact excipient form or Interaction with DS excipient phase functionality ? or formulation composition 18
  19. 19. Where do we go from here ? • Industry • Know and understand raw materials • Choose Wisely • Be aware of changes that can occur as a result of processing • Screen and investigate • Academia • Characterize complex interactions related to excipient performance and solid state variation • Tools to interrogate functional performance. • Manufacturers • Control, measure and inform • Pharmacopeial Harmonization • Continue development of Compendial Standards • Common characterization methodology and guidanceAcknowledgements: Dabing Chen @ BIPI for the Arginine Data 19

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