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Production/Formulation, Design, Process Development and Pilot-Scale Testings A. Preformulation 1 . Background Informat

Production/Formulation, Design, Process Development and Pilot-Scale Testings A. Preformulation 1 . Background Information 2. Bulk Characterization 3. Solubility Analysis 4. Stability and Compatibility B. Formulation Studies 1. Formulation Design and Trial Manufacturing

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Production/Formulation, Design, Process Development and Pilot-Scale Testings A. Preformulation 1 . Background Informat

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  1. Production/Formulation, Design, Process Development and Pilot-Scale Testings A. Preformulation 1. Background Information 2. Bulk Characterization 3. Solubility Analysis 4. Stability and Compatibility B. Formulation Studies 1. Formulation Design and Trial Manufacturing 2. Package Development and Comparative Stability 3. Process Development, Proposed Product Pilot Testing, Stability Studies, and Master Batch Documentation Development

  2. A. Preformulation: 前導配方 It can be defined as an investigation of physical and chemical properties of drug substances—alone; and combined with excipients. Collecting information For developing stable and bioavailable dosage forms Beginning in the early development of a new drug substances (biological screening stage, 生物篩選期) For selecting an suitable candidate (new compound) for further development.

  3. 1. Background Information Chemical structure, Different salts Therapeutic class and anticipated dose Supply situation and development schedule Stability-indicating assay Nature information: Organoleptic properties, Purity Essential Information a. Compound identity b. Structure c. Formula and MW d. Therapeutic indication: Probable human dose, Desired dosage forms, Bioavailability models, Competitive products

  4. e. Potential hazards f. Initial bulk lots g. Analytical Methods: GC-MS, HPLC-tandem MS, HPLC, TLC, UV/VIS spectroscopy, Synthetic route, Probable decay products h. Key dates: Bulk scale-up, Toxicology start date, Clinical supply preparation, IND filing, Phase I testing i. Critical development issues

  5. Salts used in Pharmaceutical Products in the USA (through 1974) Anion % Anion % Anion % Acetate 1.26 Benzenesulfonate 0.25 Benzoate 0.51 Bicarbonate 0.13 Bitartrate 0.63 Bromide 4.68 Calcium edetate 0.25 Camsylate 0.25 Carbonate 0.38 Chloride 4.17Citrate 3.03 Dihydrochloride 0.51 Edeate 0.25 Edisylate 0.38 Estolate 0.13 Fumarate 0.25 Gluceptate 0.18 Gluconate 0.51 Glutamate 0.25 Glycollylarsanilate 0.13 Hexylresocinate 0.13 Hydrobamine 0.25 Hydrobromide 1.90 Hydrochloride 42.98 Hydroxynaphthoate 0.25 Iodide 2.02 Isethionate 0.88 Lactate 0.76 Lactobionate 0.13 Malate 0.13 Maleate 3.03 Mandelate 0.38 Mesylate 2.02 Methylbromide 0.76 Methylnitrate 0.38 Methylsulfate 0.88 Mucate 0.13 Napsylate 0.25 Nitrate 0.64

  6. Salts used in Pharmaceutical Products in the USA (through 1974) Anion % Anion % Anion % Pamoate (Embonate) 1.01 Pantothenate 0.25 Phosphate/diphosphate 3.16 Polyglacturonate 0.13 Salicylate 0.88 Stearate 0.25 Subacetate 0.38 Succinate 0.38 Sulfate 7.46 Tannate 0.88 Tartrate 3.54 Teoclate 0.13 Tiethiodide 0.13 Cation % Cation % Cation % Organic Benathine 0.66 Chloroprocaine 0.33 Choline 0.33 Diethanolamine 0.98 Ethylenediamie 0.66 Meglumine 2.29 Procaine 0.66 Metallic Aluminum 0.66 Calcium 10.49 Lithium 1.64 Magnesium 1.31 Potassium 10.82 Sodium 61.97 Zinc 2.95

  7. Organoleptic Properties of Pharmaceutical Powders Color Odor Taste Off white Pungent Acidic Cream yellow Sulfurous Bitter Tan Fruity Bland Shiny Aromatic Intense Odorless Sweet Tasteless

  8. 2. Bulk Characterization Crystallinity and Polymorphism Hygroscopicity Fine Particle Characterization Bulk Density Powder Flow Properties Crystallinity and Polymorphism晶體性質 及 多形現象 Habit: the outer appearance of crystal Internal Structure: the molecular arrangement within solid Characterization of a solid form: a. Verifying the solid b. Characterizing the internal structure c. Describing the habit of the crystal

  9. Chemical Compound Habit Internal Structure Crystalline Amorphous Single entity Molecular Adducts polymorphs Nonstoichiometric stoichiometric Inclusion compounds solvates (hydrates) Channel Layer Cage (Clathrate) Outline of differentiating habit and crystal chemistry of a compound

  10. Different habits

  11. Analytical Methods for Characterization of Solid Forms (Methods and material required) Microscopy 1 mg Using polarizing filters, Isotropic: single refractive index; anisotropic: 2 refractive indices Fusion Methods 1 mg With polarizing filters for investigating polymorphism, mp, transition temperature, rate of transition Differential Scanning Calorimetry 2-5 mg Impurity, heat of fusion , transition of polymorph Infrared Spectroscopy 2-20 mg Scanning Electromicroscopy 2 mg SEM, polymorphism, solvate Thermogravimetric Analysis 10 mg Measuring change in sample weight, desolvation, decomposition Dissolution Solubility Analysis mg~g

  12. Thermogravimetric (TGA) for an acetate salts of an organic amine with two crystalline forms, anhydrous and dihydrate.

  13. Differential scanning calorimetric (DSC) for an acetate salts of an organic amine with two crystalline forms, anhydrous and dihydrate.

  14. Amorphous epicillin anhydrous Powder X-ray diffraction patterns

  15. Polymorphism Enatiotropic: One polymorph can be reversibly changed into another by varying temperature or pressure Polymorphic transition: Important in processing (drying) suspension dosage forms, and solid dosage forms Transition Temperature: The temperature for changing one polymorph to another. For determining transition T is microscopic observation of samples held at constant temperatures. Solubility-temperature diagrams.

  16. Hygroscopicity (吸濕性) Deliquescent (潮解性)materials adsorbed sufficient water to dissolve completely, such as sodium chloride, lithium chloride. Lithium chloride (dissolved and solid phase), 20 C, 15% RH Determining Hygroscopicity Samples of bulk drug placed in open containers with a thin powder bed to assure maximum exposure. The samples are then exposed to a range of controlled RH environment prepared with saturated aqueous salt solutions. Percentage-of-weight-gain data are plotted against time. Fine Particle Characterization Particle size, Shape, and surface morphology

  17. Microscope: > 3 microns, providing adequate size and shape characterization. Coulter Counter: particles dispersed in isotonic saline and determined from 0.4 to 800 microns. Sedimentation Method: Andreasen pipet or particle analyzer. Determination of Surface Area: BET method (Brunaurer, Emmet and Teller theory), a layer of nitrogen molecules in adsorbed to the sample surface at –196 C, liquid nitrogen boiling point (16 square Å/Nitrogen molecule). Surface Morphology: SEM

  18. Solubility of hydrocortisone and hydrocortisone 21-heptanoate in propylene glycol-water mixture

  19. Bulk Density Apparent bulk density: determined by pouring presieved (40-mesh) bulk drug into a graduated cylinder via a large funnel and measuring the volume and weight. Tapped density: determined by placing a graduated cylinder containing a known mass of drug or formulation on a mechanical tapper apparatus which is operated for a fixed number of taps (about 1000) until the powder bed volume has reached a minimum. Bulk density is important for the size of capsule product.

  20. Powder Flow Properties Affecting Factors: particles size, density, shape, electrostatic charge and adsorbed moisture. Static Angle of Repose: 25-45, lower value indicating better flow characteristics. The apparatus for measuring angle of repose.

  21. Flow rate apparatus A grounded metal tube, drug flows through an orifice onto an electronic balance which connected to a strip chart recorder. Flow rate (g/sec) is determined at each of a variety of orifice sizes (1/8 to ½ inch). Compressibility The ability of powder to form a compact under pressure. % compressiblity = 100 (Dt - Di) /Dt Dt: tapped bulk density; Di: initial bulk density

  22. Compressibility and Flowability of Pharmaceutical Excipients % Compressibility Flowability % Compressibility Flowability 5-15 Excellent 12-16 Good 18-21 Fair-Passable 23-35 Poor 33-38 Very poor <40 Very, very poor Material Flowability Material Flowability Celutab 11 Excellent Emcompress 15 Excellent Star X-1500 19 Fair-passable Lactose H2O 19 Fair-passable Maize Starch 26-27 Poor Dicalcium phosphate 2 H2O (coarse) 27 Poor Magnesium stearate 31 Poor Titanium dioxide 34 Very poor Dicalcium Phosphate, 2 H2O (fine) 41 Very, very poor Talc 49 Very, very poor

  23. 3. Solubility Analysis Solid drugs administrated orally for systemic activity must dissolve in the GI fluids prior to absorption. Compounds with an aqueous solubility of greater than 1% w/v are not expected to present dissolution-related absorption problem. Media: isotonic chloride and acidic pH 0.9% NaCl 0.01 N HCl 0.1 N HCl 0.1 M NaOH, pH 7.4 buffer at 37 C Solubility Studies: pKa, temperature effect, pH solubility profile, solubility products, solubilization mechanisms and rate of dissolution.

  24. Solubility Measurements HPLC, UV spectroscopy, Fluorescent spectroscopy and Gas chromatography pKa determinations For acidic compounds pH = pKa + log [(ionized drug)/(un-ionzed drug)] For basic compounds pH = pKa + log [(un-ionzed drug)/(ionized drug)] Methods: determining the spectral shifts by UV or visible spectroscopy, Potentiometric titration COOH

  25. Effect of Temperature Endothermic: increasing temperature, increasing solubility Exothermic: increasing temperature, decreasing solubility ln S = - Hs / RT + C S= molar solubility at temperature T R= Gas constant Hs= Heat of solution

  26. Plot of hydrochloride and free base solubilites for etoxadrol, an organic amine Etoxadrol Anesthetic C6H5 O C2H5 H N

  27. Salt Solubility Different salts with different characteristic equilibrium solubilites. Apparent solubilities in water at 25 C of salt form of -(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene methanol [antimalarial agent] Salt form Apparent solubility (g/L) Free base 0.007~0.008 Hydrochloride 0.012-0.015 D,L-lactate 1.8~1.9 2-Hydroxyethane-1-sulfonate 0.62 Methanesulfonate 0.3 Sulfate 0.020

  28. Solubilization Drug with poor water solubility or insufficient solubility for projects solution dosage forms, preformulation studies need identify possible mechanism for solubilization. Cosolvents, such as ethanol, propylene glycol and glycerin may be used. Partition Coefficient The gastrointestinal membranes are largely lipoidal in character, the lipid solubility of a drug is an important factor in the assessment of its absorption potential. The partition coefficient is defined as the ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium: Po/w = Coil /Cwater Organic solvent: chloroform, ether, amyl acetate, n-octanol

  29. Comparison between colonic absorption and Lipid/water partition of the un-ionized forms of barbiturates Barbiturates Absorbed % Chloroform/water Barbital 12 0.7 Aprobarbital 17 4.0 Phenobarbital 20 4.8 Allylbarbituric acid 23 10.5 Butethal 24 11.7 Cyclobarbital 24 18.0 Pentobarbital 30 23 Secobarbital R1=allyl 40 50.7 Hexethal 44 >100.0 H N O O R1 N R2 O R1= -C2H5 -allyl

  30. Dissolution Factors for affecting dissolution of drug particles: Chemical form Crystal habit Particle size Solubility Surface area Wetting properties Noyes-Whitney equation dC/dt = DA/hV (Cs – C) D: diffusion coefficient h: thickness of the diffusion layer A: Surface area of drug Cs: Saturated concentration Intrinsic dissolution rate constant can be determined using a constant surface area dissolution apparatus. K = D/h Cs

  31. Constant-surface assembly for the determination of intrinsic dissolution rates

  32. 4. Stability Analysis Stability studies include both solution and solid state experiments under condition typical for the handling, formulation, storage, and administration of a drug. A meaningful chemical stability study need a specific assay. Stability in toxicology formulation Solution stability The effects of pH, ionic strength, cosolvent, light, temperature and oxygen The extremes pH and temperature (0.1 N HCl, water and 0.1 N NaOH all at 90 C) for confirming decay. Assay specificity and for estimating maximum rates of degradation.

  33. The ionic strength of an isotonic 0.9% sodium chloride solution is 0.15. Cosolvent selected from the alcohol family. Solution is studied in flame-sealed ampoules and stored in variety of temperatures. In light stability test, solution is packaged in amber and yellow-green glass containers. For oxidation, samples are tested as following: a. With excessive headspaces of oxygen b. With a headspace of and inert gas such as helium or nitrogen c. With an inorganic antioxidant, such as sodium metabisulfite d. With organic antioxidant, such as BHT (butylated hydroxytoluene)

  34. Sample scheme for determining the bulk stability profile Storage Condition 4 8 12 weeks 5 C –Refrigerator 22 C—Room temperature 37 C—Ambient Humidity 37 C/ 75% RH Light Box: Control, Clear Glass, Amber Glass, Yellow-green Glass 50 C—Ambient Humidity, O2 Head Space, N2 Head Space 70 C—Ambient Humidity 90 C—Ambient Humidity

  35. An Arrhenius plot is constructed by plotting the logarithm of the apparent decay rate constant versus the reciprocal of the absolute temperature. ln K = - Ea/RT + C Ln K Slope= -Ea/R Shelf-life (t10 ) is calculated from the following equation: t10 = - ln 0.90/K = 0.105 /K 1/T ( oK)

  36. Solid State Stability The objectives are used to identify stable storage condition for drug in the solid state and identify compatible excipients for a formulation. Assay for solid state reaction: IR, DSC HPLC The decay process may be analyzed by either zero-order or first-order for less than 15-20% decay. Humidity affecting drug stability: KH = [gp1] Ko KH : apparent decay rate constant gp1: grams of water per liter of dry air Ko: decay rate constant at zero RH

  37. Compatibility Studies Tablet contains binders, disintegrant, lubricants, and fillers. Compatibility screening for a new drug must consider two or more excipients from each class. Thermal analysis (DSC, DTA) is useful in the investigation of solid-state interactions. Diffuse Reflectance Spectroscopy

  38. B. Formulation Studies 1.Formulation Design and Trial Manufacturing 2. Package Development and Comparative Stability 3. Process Development, Proposed Product Pilot Testing, Stability Studies, and Master Batch Documentation Development

  39. High-performance double rotary tablet press—Korsch PharmapressR: 1 million tablets/hr (regularly 600,000~800,000/hr)

  40. (1). Formulation Design & Trial Manufacturing Example: Tablets Tablet: Resistance to mechanical abrasion or friability, rapid disintegration and dissolution. Producing a safe, effective and highly reliable products Tablet formulation and design: The process whereby the formulator insures that correct amount of drug in the right form is delivered at over the proper time at the proper rate and in the desired location, while having its chemical integrity protected to that point.

  41. (I). Preformulation Studies 1. Stability (solid state): light, temperature, humidity 2. Stability (solution): excipient-drug stability 3. Physicomechanical properties: particle size, bulk and tap density, crystalline form, compressibility, photomicrographs, melting point, taste, color, appearance, odor. 4. Physicochemical properties: solubility and pH profile of solution/dispersion 5. In vitro dissolution: pure drug, pure drug pellet, dialysis of pure drug, absorability, effect of excipients and surfactants.

  42. (II). A Systemical Approach to Tablet Product Design 1. Identification of the optimum site for drug release along the gastrointestinal tract for the particular drug 2. Identification of the method of manufacture 3. Selection of compatible formula candidate ingredients 4. Preparation of trial formulations for in vitro and in vivo evaluation 5. In vitro testing 6. In vivo testing in animals and man, or man directly 7. Development of stability, bioavailability, validation, and other data as a required for new drug under an NDA

  43. (III). Tablet Compositions and Additives Active Ingredients 1. General considerations 2. Bioavailability considerations Nonactive Ingredients Diluents: lactose USP; lactose USP, anhydrous; lactose USP, spray-dried; starch USP; directly compressible starch; mannitol USP; sorbitol; microcrystalline cellulose; dibasic calcium phosphate dihydrate; sucrose-based diluent; sucrose USP powder; calcium sulfate dihydrate; calcium lactate trihydrate granular RC N H RCHO H2N COOC2H5 COOC2H5

  44. Binders and Adhesives Disintegrants Lubricants: Water-insoluble; Water soluble Antiadherents Glidants Colorants Flavors and Sweeteners

  45. (IV).Methods of Manufacture Compressed tablets Sublingual tablets, chewable tablets, effervescent tablets, layer tables, sustained-release products, sugar coated tablets, film coating tablets, enteric-coated tablets. Methods: Wet granulation, dry granulation and direct compression Wet granulation Advantages 1. Improving the cohesiveness and compressibility of powders 2. Suitable for high-dosage drugs having poor flow or compressibility properties

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