Handbook Of Pharmaceutics Scientists And Reviewers.pdf

1 HANDBOOK OF PHARMACEUTICS For Pharmaceutical Scientists and Reviewers Compiled & Edited Masih Jaigirdar 2 Preface Pharmaceutics is the discipline of pharmacy that deals with the process of turning a[.]

HANDBOOK OF PHARMACEUTICS Compiled & Edited: Masih Jaigirdar For Pharmaceutical Scientists and Reviewers Preface Pharmaceutics is the discipline of pharmacy that deals with the process of turning a new chemical entity (NCE) or old drugs into a medication to be used safely and effectively by patients It is also called the science of dosage form design There are many chemicals with pharmacological properties, but need special measures to help them achieve therapeutically relevant amounts at their sites of action Pharmaceutics helps relate the formulation of drugs to their delivery and disposition in the body Pharmaceutics deals with the formulation of a pure drug substance into a dosage form Branches of pharmaceutics include: Pharmaceutical formulation Pharmaceutical manufacturing Dispensing pharmacy Pharmaceutical technology Physical pharmacy Bio-Pharmaceutics Pharmaceutical jurisprudence Pure drug substances are usually white crystalline or amorphous powders Before the advent of medicine as a science, it was common for pharmacists to dispense drugs as is Most drugs today are administered as parts of a dosage form The clinical performance of drugs depends on their form of presentation to the patient Though the subject Pharmaceutics is only studied or in the educational curricula of the College of Pharmacy in different universities across the globe, but its use and at least some knowledge is needed or essential for the other technical disciplines personnel in the pharmaceutical industry as a formulator, analyst, process engineer and regulatory affairs It is also very important for a reviewer in the regulatory agency, going through the section P.3 Drug Product and Process Development of the application, to understand the basics of pharmaceutics for authentic endorsement or approval of an application from quality perspective This Hand book of Pharmaceutics is a reference work containing a compilation of information collected and edited by the initiator and made it easy by using his education in pharmaceutics and 45 years of professional experience; with over 10 years in the public service as CMC reviewer and 35+ years in the private sector (Pharmaceutical Industry) as Product Development Scientist, writing and collecting many scientific articles and giving many presentations to the audience at the scientific seminars of ISPE and AAPs and for the training as a mentor of the FDA CMC reviewers For this task of compilation the editor has utilized his own exposure and experience in the field by covering multiple subjects and technologies in a way that would not be merely a review of the literature but in depth review and interpretation Each chapter begins by assuming either the reader is not very familiar with the subject or would be a refresher P.S: This version of the Handbook of Pharmaceutics is only for the use of academic and scientific purpose and only its electronic or printed copies may be distributed among the user but not to be published by anybody for their financial benefit without the permission of the editor About the Compilation and Editor Masihuddin Jaigirdar by profession a Pharmaceutical Scientist, before retiring, was a senior Quality Reviewer, US Federal Government (G.S-14-8) with FDA/OPQ/OPMA Division III Beside his quality reviews of many applications including INDs, NDAs and over 500 ANDAs/Amendments for a period of over ten years; he has also contributed/participated in FDA OGD/OPMA various scientific working groups as a team member In October 2020 for his dedication to the FDA through his 10 years of exemplary service as an exceptional employee and mentor, received the certificate of appreciation from the CDER; FDA He has M Pharm and Post Graduate Education in Pharmaceutical Science/Technology and over 35 years of diverse experience in the Pharmaceutical Industry in the field of Formulation Development, Process Technology Transfer, Process Optimization, and Scale-up of products and Manufacturing for Brand and Generic Pharmaceuticals in US and Overseas (Europe & Middle East) As a formulation scientist he has proven success of generating many Abbreviated New Drug Applications (ANDAs) of Paragraph IV Paradigm defending them at litigation and got agency approval He has worked for many worlds reputed Pharmaceutical Companies He was the Associate Director and Research Leader of R&D Product Development; expertise in Modified Release Technology for Actavis (former Watson) Pharmaceuticals in Corona, California Masih was Senior Principal Scientist, for the generic division of Marion Merrill Dow (MMD), Hoechst Marion & Russel, Aventis; (Chelsea Laboratories), in Cincinnati, Ohio Just before joining FDA in September 2010, he was with the Product Development Group of Mylan, in Morgan Town, West Virginia GLOBAL EXPOSURE: Masih started his professional career in early 70’s, joining the then E.R.Squibb & Sons in their overseas pharmaceutical plant in Bangladesh In the 80’s was trained by ASTRA Development AB, Sodertalje, Sweden, for the position of Head of Process Technique/Technology Transfer, for the newly build pharmaceutical plant KIPICO of the Kuwait (Middle East) government He was responsible and conducted the Validation Program for Product’s Process: Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) in conjunction with technical experts from ASTRA Sweden for all pharmaceutical dosage forms Provided technical support and troubleshooting to existing products and process Has written and revised production methods, batch production records, SOPs and validation protocols Field of Knowledge/Experience/Exposure/Expertise Solid Oral Dosage: Immediate Release, Modified Release (Controlled Release & Delayed Release) Semi Solids: Ointment, Cream, Gel and Suppositories Technologies Liquids: Internal-Liquid (Oral Solution, Suspension, Elixirs, and Emulsion); Injectable: SVP & LVP, Peritoneal Dialysis and Hemodialysis solutions, ophthalmic preparations and Nasal Spray etc Contribution and Accomplishments Masih was routinely sought out by his peers for his insight on both scientific and regulatory challenges when reviewing applications (e.g., scale-up considerations for a variety of finished dosage forms) and has trained and mentored a number of Chemistry Reviewers He has been a routine trainer for new reviewers in multiple offices within the Office of Pharmaceutical Quality (OPQ); and has presented training sessions on many manufacturing process related topics He provided valuable input and actively participated in a number of important working groups and committees that had a direct impact on review work being completed in OGD, and OPQ, including OGD’s Quality by Design (QbD) Working Group and OGD’s Risk Assessment Team, and OPF’s Continual Learning Committee Masih was also well regarded for his mentorship and training abilities which have been shared across multiple offices When in the Office of Generic Drugs (OGD) he presented and participated in Study Lunch Series, served on the Training Faculty for new review chemists that formally trained approximately 65 new chemists, and served as official mentor for his division During his tenure in the Office of Pharmaceutical Quality (OPQ), he continued to serve on a Continual Learning Committee that emphasizes and enhances review and inspection processes For this endeavor he received a Leadership Excellence Award in 2016 Awards: Masih has received many awards during his 10 years’ service with the agency    Certificate of Appreciation for valuable service to the AAPS Modified Release as Learning Opportunity Manager, in November 2020 – November 2021 Certificate of Appreciation for dedication to the FDA through his 10 years of exemplary service as an exceptional employee and mentor, October 13, 2020 Award received (group): In Recognition of the OPF Training and Development Team sponsoring cross-OPQ training and development activities, December 13, 2016 • Leadership Excellence; OPF Continual Learning Committee, September 16, 2016 • Certificate of Appreciation: Risk Based Review Pilot Program, February 10, 2014 • Excellence in Mentoring: Training Faculty for New Chemist Reviewers; For outstanding efforts in training over 65 new chemists in the review of Chemistry, Manufacturing, and Control portion of the ANDA in 2013 • OGD Chemistry Risk-Based Review Groups; for demonstrating the feasibility, effectiveness and efficiency of risk-based review in the chemistry evaluation of ANDAs • Speaker at OPF Knowledge Sharing Seminar Series • CDER Office of Generic Drugs, Certificate of Appreciation; “Role of Scale-up Strategy in Product Development and Formulation, March 14, 2011 Review and Notice to Readers It is a very nicely written handbook; Concise, yet very informative with current information I suggest that every scientist working in the pharmaceutical industry involved in dosage form development, especially one relatively new in the field and without much formal training in pharmaceutics, should read the book Indeed, since there are not many pharmaceutics programs in the academia teaching physical pharmacy and drug formulation, most of the new formulators in the industry and regulatory agencies not have pharmaceutics background I believe that they will be much benefitted by reading this book I recommend the publication of this handbook at a relatively low price so that the book gets wide circulation and acceptance by the pharmaceutical community From: Abu Serajuddin Sent: Monday, February 15, 2021 1:42 PM Abu T M Serajuddin, PhD, FAPhA, FAAPS Professor of Industrial Pharmacy St John's University 8000 Utopia Parkway, Queens, NY 11439, USA Tel: 718-990-7822 Congratulations on compiling a very nice, concise compilation of useful information in pharmaceutical development and manufacture This excellent reference book that benefits from your extensive knowledge and experience will be of particular interest and value to graduate students preparing for careers in industrial pharmacy and beginning product development specialists From: Larry Augsburger Emeritus Professor at University of Maryland Baltimore University of Maryland Baltimore Severna Park, Maryland, United States Forwarded Oct at 10:42 PM larryaugsburger@gmail.com Arrangement of Contents Chapter 1: Background Information Chapter 2: Generic New Product Introduction & Product Development Process Solid Dosage (Tablet) Chapter 3: Solid Dosage Form Chapter 4: Mixing and Granulation Solid Dosage (Powder, Tablet and Capsules) Chapter 5: Hard Gelatin Capsule Chapter Chapter 6: Soft Gelatin Capsule Chapter 7: Pharmaceutical Coating Chapter 8: Solid Dosage Manufacturing Process Testing and Sampling Considerations Chapter 9: Pharmaceutical Excipients for Solid Dosage Chapter 10 Semi-Solids Dosage Chapter 11: Liquid Dosage Chapter 12: Parenteral Medications Chapter 13: Lyophilization Process Chapter 14: Typical Pilot-scale Lab Apparatus & Equipment Chapter 15: Role of Scale-up Strategy in Product Development Chapter 1: Background Information Drugs/Medicines are used for: against disease, medical or health conditions They either come from chemical or biological source Can be broadly classified into two main as per therapeutic (Pharmacological) category: Chemo-therapeutic agents (drugs), Biological-drugs Chemo-therapeutic drugs: Drugs made of chemicals A few examples are of the following groups: Analgesics/Antipyretics; Analgesic/Hypnotics; Anti-hypertensive; Anti-diabetics; Anti-depression; Anticholesterols, etc Biologicals: Drug derived from biological source or fermentations: Anti-biotic, Vitamins etc These are well known as drug substance and are produced in bulk quantities by their manufacturer However, for doctor/physician/Nutritionist prescribe them to a patent or individual in specific quantity (dose) to be taken/used/applied per recommendation Many of these doses can be as little as a few micrograms and up to 1000mg or more The question arise how to deliver them to such specific quantity/quantities? Pharmaceutical Dosage form became the media/mode of delivery to the patient/user to take/use/apply specified quantity one time or multiple times depending on the requirement Pharmaceutical Dosage Form: Dosage forms (also called unit doses) are essentially pharmaceutical products in the form in which they are delivered for use, typically involving a mixture of active pharmaceutical ingredient (API) and inactive ingredient (excipients) Depending on the method/route of administration, dosage forms come in several types These include in general broadly in following main three groups: Solids, Liquid and Semi-solids Solids: Powder, Powder for reconstitution as solutions or suspensions, Pill, Tablet, and Capsule Semi-Solids: Ointment, Cream & Gels Various dosage forms may exist for a single particular drug: due to different medical conditions or patient population (Pediatric, adult and geriatric) can warrant different routes of administration Liquids: Internal & External Liquids Internal Liquids: Oral Solution & Suspension, Emulsion, Dialysis solution, Parenteral and Ophthalmic liquids External Liquid: Disinfectants, Sanitization Liquid, Hospital Germicidal Liquids, etc Chapter 2: Generic New Product Introduction & Product DevelopmentProcess Solid Dosage (Tablet) Generally Generic Firm will have a New Product Selection Committee (NPSC) This committee evaluate/explore before selecting and finalizing to introduce a new drug product into market These are: Strategies: Pharmaceutics, Analytical and Bio-Pharmaceutics Market Barriers: Patient & Exclusivities Market Analysis: Projected Forecast (Units, Dollars), anticipated market share based on being number 1, 2, and so forth player API availabilities Time line Stage 1: Literature Search  Literature Search  USP, BP, JP, EP, Merck, Florey etc  FDA-FOI  Summary Basis of Approval   On-line search of FDA/CDER info Data Base guidelines for test methods,  Patent Evaluation dissolution, impurities, Bio-study parameters etc  Orange Guide + FDA/CDER www.patent consultant Stage 2: API Sourcing  Sourcing of Active Pharmaceutical Ingredient (API); Drug Substance   Have Potential Supplier lists   US agent for API US & International Suppliers from (Europe, Asia, etc.) Request Technical Binder & DMF Information  Request samples & CoA and Specifications  At least two suppliers for full evaluation Stage 3: API Evaluation and Procurement   Evaluation of Active Pharmaceutical Ingredient (API) Purchase of API  At least 2-3 potential API supplier  DMF availability & Status  Compliance with USP monograph  Impurity profile and stability  Potential polymorphic forms  Commitment for physical specification (micronized)  Statement of non-patent infringement  In g/kg quantities for method development & pre- formulation study Stage 4: API Testing (Early Sample Quantity) Chemical testing by R&D Analytical Laboratory  Chemical testing as per:  USP monograph  Pharmacopeia Forum (if available)  In-house method (based on API (if present) manufacturer Stage 5: Bulk API Testing Chemical testing by R&D Analytical Laboratory  Polymorphism (Full physical & chemical characterization)  Particle size distribution & method development  Assay  Stress study (Heat, Acid, Base, Oxidative and Photolytic)  Relative substances/Impurity profile, Degradants  Optical rotation  Enantiomeric purity  O.V.I Testing Stage 6: Pre-Formulation Drug substance  Physico-Chemical testing by R&D Pharmaceutics Laboratory  Physico-chemical evaluation for:  Moisture sorption/desorption  Flowability, Particle size, B/T Density and Compact-ability study Drug Product  Drug-Excipient Compatibility study  At least different lots in smallest and largest pack size Physico-chemical evaluation of Innovator’s Product by R&D Pharmaceutics Laboratory  Evaluation of physical parameters (Shape, Size, Dimension, Score, Color, Embossing for Logo)  Container/Closure system (packaging materials, dunnage: cotton, polyester, rayon; desiccant; odor absorbent, oxygen scavenger etc.)  Physical testing for:  Weight, Thickness, Hardness, LOD, Friability, Disintegration etc  For MR Tablets: Evaluation of tablet’s disintegration behavior: Microscopic observation of Innovator’s Product by R&D Pharmaceutics  Erosion Vs Congealing characteristics  By slight crushing of tablet with a mortar & pestle and observing under microscope for:  Particles Vs granules for particle size, crystal shape & habit  Differentiation on the presence specific excipients can be verified from microscopic observation e.g., Lactose modified Vs Anhydrous Lactose, Cross-linked cellulose, Starch and Avicel have a specific shapes and morphology and maybe detected 10 Rotary Tablet Press: at least to 16 stations with pre-compression and preferably instrumented Bench Top Semi-Automatic capsule Filling Machine with change parts to handle at least sizes: 0, 1, 2, 3, & R&D Small scale (9") Coating Machine Vector: Laboratory Development Coating System (LDCS) with spray gun 10 Bench Top HDPE bottle induction sealing machine 11 Bottle Cap Torque measuring apparatus 12 Bench Top Blister Packaging Machine III for Liquid and Semi-Solid (Oral Liquid, Suspension, Emulsion, Ointment, Cream & Jelly) Jacketed Mixers (Electric or Steam) - 10 L) Bench Top Lab Mixer and Homogenizer (Electric or Pneumatic) Colloid Mill (Silverson, Fryma, Ross etc.) Triple Roll Ointment Mill Color Matching Apparatus Bench Top Semi-Automatic Cream/Ointment Collapsible Tube Filling Machine Brookfield Viscometer Specific Gravity Measuring bottles and jars Bench Top HDPE bottle induction sealing machine 10 Bottle Cap Torque measuring apparatus 114 Chapter 15: Role of Scale-up Strategy in Product Development [Solid Dosage] Scale-up factors for Diffusion Mixers Patterson & Kelley Blender • • Unit Size Cubic Feet Blend Time Factor* 1.2 1.3 1.43 1.50 10 1.70 20 1.85 30 2.00 40 2.10 50 2.20 60 2.30 75 2.50 100 2.70 Scale Up Factor for Standard Tumble Blenders (Provided by Patterson & Kelley) Scale-up for P.K blenders is accomplished by applying the scale-up factors from the previous table, to the formula below: Blending Time (Blender 2) = Factor (Blender 2) ÷ Factor (Blender1) x Blending Time (Blender 1) 115 Example: Scale up from a 5ft3 blender with minutes blending time to a 30ft3 blender, the blending time will be: (2 ÷ 1.5) x = 6.66 minutes ~ minutes For P.K blenders a consistent blend can be expected in a range from +5% to 30% of the rated volume, although this will vary by product Gemco Blender: Another simple “rule of thumb” for diffusion type blenders is to count vessel revolutions    Example: Using a cft blender, with a vessel RPM of 23 If the blend is accomplished in 10 minutes the vessel will complete 230 revolutions Moving to a larger blender the same number (230) revolutions will be required A 40 cft blender turning at 12 RPM will need (230÷12) = 19.5 minutes to blend The blend time will increase due to the fact that the larger the blender, the slower the vessel rotation So, for scale-up, matching of rpm or time of the two blenders will be incorrect For Gemco Blender: SC: 33 -100% and DC: 50-100% capacity High-Shear Mixer Granulator   Rotational speeds (RPM) in combination with vessel/impeller diameter give almost the same circumferential speed (Tip Speed) For scale-up, it is very important to have same or almost same Tip speed (meter/second) of the mixer/impeller between the equipment Scale-up Parameters: For scale-up in a high-shear mixer it is important to check the same tip speed of the impeller between the equipment 116 Collette Gral 10 25 75 150 300 400 600 1200 Working Capacity (L) 17 50 100 200 267 400 800 Impeller radius (cm) 11.9 18 25.4 33.5 40.0 46.0 52.5 72.5 Impeller Speed (rpm) Low/High 420/ 630 285/ 425 200/ 305 145/ 225 125/ 185 105/ 155 95/135 75/115 Impeller Tip speed(m/sec) 5.5/ 8.4 5.4/ 8.2 5.5/ 8.4 5.4/ 8.2 5.4/ 8.2 5.06/ 7.47 5.4/ 8.0 5.8/ 8.9 Chopper Speed Speed I : 1500 rpm Speed II: 3000 rpm 1300/ 2600 1200/ 2400 T.K Fielder 10 25 65 150 300 400 600 1200 Working Volume (L) 2, 4.5 &6 15 40 100 240 320 480 900 Impeller Speed (rpm) Low/High 334/ 668 261/ 522 209/ 418 130/ 260 108/ 216 98/ 196 86/172 68/136 Impeller Tip speed(m/sec) 5.2/ 10.4 5.6/ 11.2 5.5/ 11.0 5.0/ 10.0 5.3/ 10.6 5.3/ 10.6 5.3/ 10.6 5.3/ 10.6 Chopper Speed Speed I : 1800 rpm Speed II: 3600 rpm Diosna 10 25 50 100 250 400 600 1250 Working Volume (Kg) 3-5 8-12 15-25 35-50 80-100 180-220 280-350 560-710 Impeller Speed (rpm) Low/High 215/ 433 162/ 325 133/ 265 98/ 196 88/ 176 64/ 129 57/ 114 55/ 75 Impeller Tip speed(m/sec) Not Available Note: Impeller Speed is slower going from small to large Equipment This is to keep same tip speed 117 Scale Up Factors in Fluid Bed Processing (Granulation and Drying) Granulating A Critical Parameters ▪ Air flow - ft.3 /min ▪ Air velocity ft /min ▪ Air temperature degrees F or C ▪ Total amount of liquid - kgs ▪ Spray rate - g/min ▪ Atomizing pressure - psi ▪ Fluidized bed depth - inches/mm ▪ Nozzle height above bed 118 B Theoretical Scale Up ▪ Use same inlet temperature ▪ Use same velocity - velocity calculation Air flow ft.3 /min Ft.2 of distributor plate = ft./min ▪ Calculate total amount of liquid per kg of product processed and maintain ▪ Calculate spray rate per CFM and maintain ▪ Maintain same liquid droplet size by adjusting air pressure as required ▪ Maintain same bed height ▪ Maintain nozzle height above bed C Practical Tips ▪ visually achieve same fluidization level ▪ Note that deeper bed will result in denser granule ▪ In small R&D machines (up to 20 liters) the nozzle may be closer to the bed The lower liquid addition rate and smaller nozzle will produce a smaller droplet size to compensate The nozzle height may need to be adjusted upwards when scaling up from small R&D to larger systems Tablet Press Scale-up: To have same dwell time between the Tablet Press Calculation of Dwell Time for Scale-up DT = Dwell Time Time = Distance = Punch Head flat diameter TPM = tablet per minute Velocity PCD = Turret Pitch Circular Diameter Π = 3.14159 Number of Stations = # of stations in the turret Velocity = TPM x Π X PCD = TPM x 3.14159 x 228.6 = 0.748 TPM (mm/sec) (#Stations) x 60 16 x 60 Dwell Time = Head flat dia = m ÷ m/sec = sec Velocity Example: BETAPRESS 16 PCD = 228.6mm Head Flat Dia for a B tooling = 12.7 mm; Head Flat Dia for a D tooling = 18.2 mm DT = 12.7mm = 16.978 = 17 0.748 TPM For Press Speed of 1400 TPM: DT = 17÷1400 = 0.73 seconds Scale-up Pan Coating RPM for Larger Pan = (Pan rpm small) x [ (diameter of small pan) ÷ (diameter of large pan) ] Thermodynamic Analysis of Aqueous Coating (used for scale-up) 119 Practical Example Critical aspects of Product Development (Solid Dosage) by D.C method of manufacture; Choice and role of Excipient A drug product as a dosage form would contain both drug substance (Active Pharmaceutical Ingredient) and excipients added to aid the formulation and manufacture of the dosage form for administration to patients In fact, the properties of the final dosage form (i.e its bioavailability and stability) are, in major case highly dependent on the excipient used, their concentration and interaction with both the API and each other Hence, excipients should not be considered as inert or inactive ingredients It is therefore, needed to know and understand not only their Physico-chemical properties but also the role play chosen (novel forms of delivery) for the formulation Drug substance  Physico-chemical evaluation for:   Moisture sorption/desorption  Followability, Particle size, B/T Density Physico-Chemical testing by R&D Pharmaceutics Laboratory and Compact-ability study  Drug-Excipient Compatibility study API solid–form screening and characterization is a crucial part of drug substance development and pre–formulation Knowledge of the underlying fundamentals of polymorphism, hydrates/solvates, salts, and co-crystals is essential to establish an understanding of a drug substance and its solid–form throughout the drug development lifecycle Critical aspects of Product Development (Solid Dosage) by D.C method of manufacture; Choice and role of Excipient A drug product as a dosage form would contain both drug substance (Active Pharmaceutical Ingredient) and excipients added to aid the formulation and manufacture of the dosage form for administration to patients In fact, the properties of the final dosage form (i.e its bioavailability and stability) are, in major case highly dependent on the excipient used, their concentration and interaction with both the API and each other Hence, excipients should not be considered as inert or inactive ingredients It is therefore, needed to know and understand not only their Physico-chemical properties but also the role play chosen (novel forms of delivery) for the formulation Drug substance  Physico-Chemical testing by R&D Pharmaceutics Laboratory  Physico-chemical evaluation for:  Moisture sorption/desorption  Followability, Particle size, B/T Density 120 and Compact-ability study  Drug-Excipient Compatibility study API solid–form screening and characterization is a crucial part of drug substance development and pre–formulation Knowledge of the underlying fundamentals of polymorphism, hydrates/solvates, salts, and co-crystals is essential to establish an understanding of a drug substance and its solid–form throughout the drug development lifecycle Critical factors considered for the Formula and Process design for solid dosage Drug load and API Physico-chemical characteristics/attributes evaluated by the R&D Pharmaceutics I Low drug load < 5.0% in the product formula for a D.C method of manufacture In such case it is very important to evaluate the APIs cohesiveness and/or binding property Depending on this characteristic the formulator has to Selective mixing of the low drug load 5.0% - 50% of low compaction property In such case either a pre-mix with a binder and/or cohesive property excipient either premixed, dry granulated under high pressure without the use of a liquid using one of the following processes Generally conducted by: Making large size tablet (Slug) in a tablet press/slugging or passing the powder material between two counter rotating rollers producing sheet or ribbon by a roller compactor/Chilsonator Then the intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size granules The unused fine material may be reworked to avoid waste In the next step a flow property enhancer; either Lactose Monohydrate or combination with Microcrystalline Cellulose (Avicel) of right grade depending on the pre-formulation study of the 121 API is ad-mixed by ordered mixing operation with other functional excipients, disintegrant and lubricant This will provide not only the flow property but also maintain the blend uniformity III High drug load > 50% with not only very low compaction property but also efflorescence property In such case, a selective mixing of high drug load >50% API of non-cohesive property with a cohesive ingredient is done to induce compaction for a Direct Compression (D.C) Process, mostly by two processes; a) Moisture Activated Dry Granulation (MAD-Granulation): This process involves moisturizing the powder blend to a pre-determined LOD to achieve compaction for a direct compression (D.C) method of manufacture b) Hot-Melt Granulation: In these process molten materials is used as the granulating liquid API is either co-melted or dispersed in the molten stage of the vehicle and then cooling it to solidification This process is used mainly for the following purpose • • • • • • • For poorly soluble API for enhancing solubility and dissolution To protect moisture sensitive API To achieve sustained or extended release API or formulation ingredients are moisture sensitive Unable to withstand elevated drying temperature Formulation ingredients has sufficient inherent binding cohesive properties To improve flow property and die filling 122 An Example of Product Development Employing Moisture Activated Dry-Granulation Drug Substance: Metformin HCl Drug Load: ~ 94% Evaluated Pre-formulation Physio-chemical Properties:        Metformin HCl drug substance by itself is a white, clumpy powder, with no flow-ability and/or compactibility characteristics (for all vendors) Pre-milled API from the supplier had comparatively a better flow-ability It is was found critical to use milled metformin HCl with the particle size, particle size distribution and the bulk density that was found with the latest material from the supplier FarmHispania “Milled” metformin HCl supplied by FarmHispania had the following particle size, particle size distribution and bulk density  50.2 % ≤ 180 um  32% ≤150 um  2.8% ≤75 um  Bulk density of 0.36/mL Use of the milled material achieved process ease tablet formula for the drug product Blending with 1% colloidal silicon dioxide has radically improved the flow property; however it did not improve its compactibility characteristics significantly Microcrystalline Cellulose, Avicel PH 112 of a nominal mean particle size of 100µm and moisture content ≤ 1.5% was used for the MAD process to ultimate moistened it to ≤ 5.0%; which is same as the Avicel PH 102 Hence, there was about (5.0 – 1.5) 3.5% moisture (water) available for the moisture activated dry granulation A few experiments were made using a small scale PMA-I high-shear mixer using formulation with drug and excipient except lubricant and spraying water to obtain a dry granulation with moisture content of approximately 2-4% This granulation without further processing (i.e drying & milling etc.) was blended with a lubricant and then compressed into tablets Incorporating a liquid type of humectant (polyethylene glycol 400 or Glycerol) in the formula would also help to keep the required moisture for efflorescence type of API, e.g Escitalopram Since metformin HCl being almost 94% in the formula and does not have any compactibility, this is also attributed to its very low moisture content Therefore, a moisture activated drygranulation method was employed to make some tablets Following was the method and adjuvant that were tried for the approach Method: Moisture Activated Drygranulation/Direct Compression Binder: Dissolution aid: Lubricant: Bulking Agents: Hydroxypropylcellulose, povidone and methylcellulose Sodium starch glycolate Magnesium stearate or Stearic acid Microcrystalline cellulose, Avicel PH 112 finally converting it into PH102 by MAD process Hydroxypropyl methylcellulose Polyethylene glycol Water Tablet Coating agents: 123 Physio-chemical characterization at Product Development Stage; specifically for solid dosage drug products API solid–form screening and characterization is a crucial part of drug product development and pre– formulation Knowledge of the underlying fundamentals of polymorphism, hydrates/solvates, salts, and co-crystals is essential to establish an understanding of a drug substance and its solid–form throughout the drug development lifecycle These are as follows: Moisture sorption/desorption Followability Particle size & Particle size Distribution Bulk and Tap Density Compact-ability study Drug-Excipient Compatibility study The challenges faced for API with very low and high bulk densities for formulation of tablets by direct compression method of manufacture Case History Ranitidine HCl: The API had Low bulk density: 0.22g/mL The API related problem and their resolution It was found that the API ranitidine HCl by itself is compactible and it is possible to make a direct compression formula It is also sticky in nature but had a low bulk density of ≤ 0.22g/mL Because of the relatively high dose of the API and its low flow-ability it is likely to cause some significant problems for a direct compression formula However, introducing a pre-mix step for the API with 1% Colloidal Silicon Dioxide and screening through a 14 mesh changed the angle of repose from 42° to about 27 ° improved its flow property and ultimate tablet machine die filling to get the right weight and final content uniformity Case History Galantamine HBr: API of high density (~0.6g/mL) Segregation Characteristics of Galantamine HBr and resultant dry blend for direct compression had blend uniformity problem resulting in tablet’s Content Uniformity problem   Selectively mixing Galantamine HBr with a right proportion of Microcrystalline Cellulose, (Avicel PH 301) with a bulk density of about 0.45g/mL and colloidal silicon silicone dioxide Avicel PH 301 grade of microcrystalline cellulose in the formula provided/mitigated for BU &CU Hence, the Physio-Chemical Evaluation & testing of Drug Substance by R&D Pharmaceutics Laboratory was found for these two projects 124 Modified Release Technology (Solid Dosage) Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage) or a drug with a delay after its administration (delayed-release dosage) Sustained-release dosage forms are dosage forms designed to release (liberate) a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates (an example being hydrogels) Sustained release's definition is more akin to a "controlled release" rather than "sustained" Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage SR maintains drug release over a sustained period but not at a constant rate CR maintains drug release over a sustained period at a nearly constant rate.[1] Sometimes these and other terms are treated as synonyms, but the United States Food and Drug Administration has in fact defined most of these as different concepts.[1] Sometimes the term "depot tablet" is used by non-native speakers, but this is not found in any English dictionaries and is a literal translation of the term used in Swedish and some other languages Modified-release dosage and its variants are mechanisms used in tablets (pills) and capsules to dissolve a drug over time in order to be released slower and steadier into the bloodstream while having the advantage of being taken at less frequent intervals than immediaterelease (IR) formulations of the same drug For example, extended-release morphine enables people with chronic pain to only take one or two tablets per day Most commonly it refers to time dependent release in oral dose formulations Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g to target different regions of the GI tract) etc A distinction of controlled release is that not only it prolongs action but it attempts to maintain drug levels within the therapeutic window to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency Functional Excipient Used for Modified Release Tablets/Capsules       Modified Release group is divided into two major classes: Extended Release & Delayed Release Excipients for Extended Release group can be classified into two major group 1) hydrophilic and 2)hydrophobic Hydrophilic Materials: Cellulosic Polymers, Gums, PVP, PEG, etc Hydrophobic Materials: Ethyl Cellulose, Wax Eudragit (RL/RS) etc These polymers are generally pH-independent Delayed Release Excipient: This is usually desired to bypass the stomach and or release of the drug to a specific site e.g Colon   Polymers generally used are mostly pH dependent Various Methacrylic Acid polymers called “Eudragit” are used They can be An-ionic, Cationic or Neutral e.g Eudragit L30D-55 is soluble ≥ pH 5.5 suitable for intestinal delivery 125   Eudragit FS30D is soluble above pH 7, hence unique for colonic delivery Also Polyvinyl Acetate Phthalates & Succinates Various Systems Used for Modified Release Technologies: Matrix System: In this system the medium or the substrate is either a dry mix or wet granulated substrate is made with the API and the polymer or combination of different type or grade of polymer to get the desired rate of release with or without other tablet compression or encapsulation aids [Flowenhancer (SiO2 and lubricant (MgS)] There could be in either hydrophilic or hydrophobic matrix formulation systems For the generic product development it is very important to conduct the Physio-chemical properties are conducted to study stability and erosion property of the blend and tablets of the brand and generic formulated subject product For in specific cases even the pH has to be evaluated at these stages Major hydrophilic polymers have the property of swelling in water and forming a gelatinous like substance and provide sustained drug release by both diffusion out of the gel and erosion of the tablet A case study history using acidified hydrophilic system: For the generic drug product it was needed to maintain a specific acidic pH for the granulated substrate and the final tablet for its final stability This was made with an acidified granulating liquid with the following variables The tablets formulated with the high molecular weight hydroxypropyl cellulose (HPC-HXF), and combination of talc, magnesium stearates as lubricant, maintained the required pH and got the required gel forming and erosion characteristics for the tablets sustained release characteristics Their initial dissolution results confirmed the affirmative effect of the polymer HPC-HXF in the hydrophilic-matrix formulation However, these tablets in their stress and accelerated stability condition observed dose dumping, but there was no degradation of the product Thus, this dissolution failure at stability study needed further evaluation Therefore, studies were required on the product formulation in conjunction with the use of HPC as the matrix polymer Aqualon the manufacturer of the polymer hydroxypropyl cellulose was contacted Aqualon and the Generic’s R&D conducted series of physio-chemical testing to investigate and find the root cause of dissolution failure and/or physical popping of the tablets in the dissolution apparatus Acid catalyzed hydrolysis is a mechanism that can occur with all cellulose ethers Celluloses are sufficiently stable towards hydrolysis for most uses including film coating and wet granulation followed by oven drying at moderate temperature conditions e.g 50-70 deg C However, they can be susceptible to hydrolysis by acids and, to a lesser extent, by alkalis Acids attack the acetyl linkages, cleaving the 1-4glycosidic bonds The hydrolysis mechanism is catalyzed by the presence of water and the rate is increased by increasing temperature The result of hydrolysis is chain cleavage, which translates to a polymer with reduced molecular weight and reduced viscosity Thus, there is a very fast in-vitro drug release 126 There are a number of variables, which influence cellulosic hydrolysis: 1) Water - Water is needed to catalyze the reaction without the presence of water the hydrolysis reaction cannot start Increased moisture and humidity levels will increase the rate at which hydrolysis proceeds 2) Temperature - It is possible that in the presence of dilute acid that at low temperatures (such as room temperature) one will not observe the hydrolysis mechanism either because it is not thermodynamically favorable or it is kinetics very slow As one goes to higher temperature the rate of hydrolysis increases This would mean that it is possible not to see a loss of polymer chain length at low temperature but only at higher temperatures Temperature is secondary as a direct variable The degradation kinetics is temperature dependent, but since everything is done at a defined relative humidity, the focus should be on the temperature dependence of the water load in the system, which just provides a greater reservoir of moisture to the system 3) Time - If the hydrolysis reaction is thermodynamically possible then the time at which the polymer is subjected to the increased temperature conditions is a variable The longer the polymer is exposed to the increased temperature conditions is the presence of the dilute acid and water at a high temperature the faster the hydrolysis rate New formulation Approach due to the problem encountered with the initial formulation in which there was a dose dumping phenomenon, which had HPC of 5% intra-granular and 5% extra granular Therefore, this 5% intra-granular HPC is more susceptible to acid catalyzed hydrolysis In the new experimental design, a minimum quantity of the HPC in the intra-granular portion of the granulation was used The reason was that more HPC extra granular will not be in contact with the dilute HCl solution and will also not be subjected to the drying process This should improve the likelihood of the polymer not cleaving due to non-exposure to moisture; dilute acid, increased temperature or drying time All of these as described earlier increase the rate of hydrolysis of the polymer Batches were made with HPC-HXF 1% intra granular and 9% extra granular in conjunction with reduced amount of diluted HCl to 2.0% w/w in the formula Tablets made with this process were subjected to both stress (50°C/75%RH) and accelerated (40°C/75%RH) stability conditions They were physiochemically tested for both pH and dissolution behavior characteristics Studies revealed that tablets of stress stability up to weeks were holding together without any popping Tablets of accelerated stability up to three months were not only holding together but also their dissolution profile matched with that of the initial time point Studies were also conducted to optimize the following factors: 1) Effect of amount of diluted HCl on product’s stability 2) Influence of LOD (dried granulation) on pH /stability 3) Effect of Polymer level on tablet’s drug release 4) Effect of polymer viscosity on tablet’s drug release 5) Effect of lubricant on the drug product’s physio-chemical attributes 127 Coating system: There are many film coating employed to achieve modified release, both sustainedrelease i.e., releasing by 12 hours, need to take two dosages a day or long term extended-release of 24 hours needs just one unit of the dosage to be taken daily These can be achieved by the following techniques: a Making a film with a screen with required porosity: Using mostly the hydrophobic polymer ethyl cellulose as the film maker and either lactose or other soluble but inert excipient by either milling, micronizing and selective sieving process for desired PSD and final porosity or door opening In most case the substrate in the unit dose itself have some matrix polymer in its formula b The CPP and CQA for these processes are; i) Molecular weight and/or viscosity of the film polymer and its amount ii) Particle size and particle size distribution of the pore former iii) Rate of addition and Speed of mixing for the pore former and the film former respectively c Making a semi-permeable membrane film; this system does not have pore former or a particular size door opening, rather the film formed itself is a semi-permeable allows the film coated unit dosage substrate to come out or dissolve into the media at a desired regulated rate based on the dissolution specification In such system requires selecting of polymers of hydrophobic and hydrophilic nature, at a specific combination, determined by optimization experiment trials, when applied to core tablet as a film coat forms a semi-permeable membrane that has a regulated drug release This will result in an extended drug release profile for about 24 hours in the selected biorelevant dissolution media matching to that of reference tablet That would ultimately help to get bio equivalency of the formulated product d Generally for the hydrophobic polymer either dehydrated ethanol, IPA or a ready-mix aqueous dispersion of Ethyl Cellulose is used Sometimes talc or MgS are used as anti-tacking agent In almost most every case the substrate in the unit dose itself is of immediate release formula The CPP and CQA for these processes are; iv) v) Molecular weight and/or viscosity of the film polymers and their amount in the desired ratio Rate of addition and Speed of mixing e Another type of secondary coating systems is also used based on food effect or a specific requirement to introduce the drug product at a specific site of the GI system A second coating is applied to the extended release coated unit dosage tablet, pellets or capsules that would will delay and/or have a lag time in the release profile of the finished unit dosage drug product in the selected bio-relevant dissolution media That will help to nullify any food effect on drug absorption and or to get it releases at the desired site of the GI system f Example: A second coating system consists of Methacrylic acid co-polymer [Eudragit L-100-55] is usually applied on top of the first coat to induce a delayed-release effect (lag time of ~ hours in 0.1N HCl) for nullifying in-vivo food effect of the drug absorption 128 ... the basics of pharmaceutics for authentic endorsement or approval of an application from quality perspective This Hand book of Pharmaceutics is a reference work containing a compilation of information... collected and edited by the initiator and made it easy by using his education in pharmaceutics and 45 years of professional experience; with over 10 years in the public service as CMC reviewer and. .. a variety of finished dosage forms) and has trained and mentored a number of Chemistry Reviewers He has been a routine trainer for new reviewers in multiple offices within the Office of Pharmaceutical