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

A. Preformulation:
It can be defined as an investigation of physical and chemical properties of drug substancesalone; 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, ) For selecting an suitable candidate (new compound) for further development.

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

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

Salts used in Pharmaceutical Products in the USA (through 1974) Anion

Acetate Bicarbonate

%
1.26 0.13

Anion
Bitartrate

%
0.63

Anion
Benzoate Bromide

%
0.51 4.68

Benzenesulfonate 0.25

Calcium edetate
Chloride Edeate Fumarate Glutamate Hydrobamine Hydroxynaphthoate

0.25
4.17 0.25 0.25 0.25 0.25 0.25

Camsylate
Citrate Edisylate Gluceptate

0.25
3.03 0.38 0.18

Carbonate
Dihydrochloride Estolate Gluconate

0.38
0.51 0.13 0.51 0.13 42.98 0.88

Glycollylarsanilate 0.13 Hexylresocinate Hydrobromide Iodide 1.90 2.02 Hydrochloride Isethionate

Lactate
Maleate Methylbromide Mucate

0.76
3.03 0.76 0.13

Lactobionate
Mandelate Methylnitrate Napsylate

0.13
0.38 0.38 0.25

Malate
Mesylate Methylsulfate Nitrate

0.13
2.02 0.88 0.64

Salts used in Pharmaceutical Products in the USA (through 1974)

Anion
Pamoate (Embonate) Polyglacturonate Subacetate Tannate Tiethiodide

%
1.01 0.13 0.38 0.88 0.13

Anion
Pantothenate Salicylate Succinate Tartrate

%
0.25 0.88 0.38 3.54

Anion
Stearate Sulfate Teoclate

%
0.25 7.46 0.13

Phosphate/diphosphate 3.16

Cation
Organic
Benathine Diethanolamine Procaine Metallic Aluminum Magnesium

%
0.66 0.98 0.66

Cation

Cation
Choline Meglumine

%
0.33 2.29

Chloroprocaine 0.33 Ethylenediamie 0.66

0.66 1.31

Calcium Potassium

10.49 10.82

Lithium Sodium

1.64 61.97

Zinc

2.95

Organoleptic Properties of Pharmaceutical Powders

Color Off white Odor Pungent Taste Acidic

Cream yellow
Tan Shiny

Sulfurous
Fruity Aromatic

Bitter
Bland Intense

Odorless

Sweet
Tasteless

2. Bulk Characterization
Crystallinity and Polymorphism Hygroscopicity

Fine Particle Characterization

Bulk Density Powder Flow Properties

Crystallinity and Polymorphism

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

Chemical Compound
Habit Internal Structure

Crystalline Single entity polymorphs

Amorphous Molecular Adducts

Nonstoichiometric
Inclusion compounds

stoichiometric
solvates (hydrates)

Channel

Layer

Cage (Clathrate)

Outline of differentiating habit and crystal chemistry of a compound

Different habits

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 Thermogravimetric Analysis 10 mg SEM, polymorphism, solvate Measuring change in sample weight, desolvation, decomposition Dissolution Solubility Analysis mg~g

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

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

Amorphous epicillin anhydrous

Powder X-ray diffraction patterns

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.

Hygroscopicity ()
Deliquescent ()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

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 /Nitrogen molecule). Surface Morphology: SEM

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

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.

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.

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 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

Compressibility and Flowability of Pharmaceutical Excipients

% Compressibility Flowability
5-15 18-21 33-38 Excellent Fair-Passable Very poor

% Compressibility
12-16 23-35 <40

Flowability
Good Poor Very, very poor

Material
Celutab 11 Star X-1500 19 Maize Starch 26-27

Flowability
Excellent Fair-passable Poor

Material
Emcompress 15 Lactose H2O 19

Flowability
Excellent Fair-passable

Dicalcium phosphate 2 H2O (coarse) 27 Poor

Magnesium stearate 31 Poor

Dicalcium Phosphate, 2 H2O (fine) 41

Titanium dioxide 34 Very poor

Very, very poor

Talc

49

Very, very poor

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
0.1 M NaOH, at 37 C

0.01 N HCl
pH 7.4 buffer

0.1 N HCl

Solubility Studies: pKa, temperature effect, pH solubility profile, solubility products, solubilization mechanisms and rate of dissolution.

Solubility Measurements HPLC, UV spectroscopy, Fluorescent spectroscopy and Gas chromatography pKa determinations For acidic compounds pH = pKa COOH

+ 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

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

Plot of hydrochloride and free base solubilites for etoxadrol, an organic amine

Etoxadrol
Anesthetic
H N C6H5 O C2H5

Salt Solubility Different salts with different characteristic equilibrium solubilites.

Apparent solubilities in water at 25 C of salt form of -(2piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene methanol [antimalarial agent]

Salt form Free base Hydrochloride Apparent solubility (g/L) 0.007~0.008 0.012-0.015

D,L-lactate
2-Hydroxyethane-1-sulfonate Methanesulfonate

1.8~1.9
0.62 0.3

Sulfate

0.020

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

Comparison between colonic absorption and Lipid/water partition of the un-ionized forms of barbiturates Barbiturates Barbital Absorbed % 12 Chloroform/water 0.7
H

Aprobarbital
Phenobarbital Allylbarbituric acid Butethal Cyclobarbital

17
20 23 24 24

4.0 O R1 4.8
10.5 11.7 18.0
R2

N
N O

R1= -C2H5 -allyl

Pentobarbital
Secobarbital R1=allyl Hexethal

30
40 44

23
50.7 >100.0

Dissolution

Factors for affecting dissolution of drug particles:

Chemical form Solubility Noyes-Whitney equation dC/dt = DA/hV (Cs C) Crystal habit Surface area Particle size Wetting properties

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

Constant-surface assembly for the determination of intrinsic dissolution rates

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.

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)

Sample scheme for determining the bulk stability profile

Storage Condition 5 C Refrigerator 4 8 12 weeks

22 CRoom temperature
37 CAmbient Humidity 37 C/ 75% RH Light Box: Control, Clear Glass, Amber Glass, Yellow-green Glass 50 CAmbient Humidity, O2 Head Space, N2 Head Space 70 CAmbient Humidity 90 CAmbient Humidity

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

Shelf-life (t10 ) is calculated from the following equation:

t10 = - ln 0.90/K = 0.105 /K

Slope= -Ea/R

1/T ( oK)

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 firstorder 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

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

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

High-performance double rotary tablet pressKorsch PharmapressR: 1 million tablets/hr (regularly 600,000~800,000/hr)

(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.

(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.

(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

(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

H2N

H RCHO RC COOC2H5

COOC2H5

Binders and Adhesives

Disintegrants Lubricants: Water-insoluble; Water soluble

Antiadherents
Glidants Colorants Flavors and Sweeteners

(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

3. Good distribution and uniform content for soluble low dosage drugs and color additives
4. Preventing segregation of components of a homogenous powder during processing, transferring and handling 5. Possible improving the dissolution rate of a hydrophobic drug

Limitation An expensive process for labor, time, equipment, energy and space requirements

Drug

Direct compression Tableting

Advantages 1. Economy

2. Elimination of heat and moisture

3. Prime particle dissociation

Grind

Blend

4. Stability
5. Particle size uniformity Limitations Flow, bonding of particles, coloring tablets

Compress

Tablet Direct Compression

Dry Granulation
Advantages 1. For mositure-sensitive materials

2. For heat-sensitive materials

3. For improving disintegration since powder particles are not bonded together by a binder

4. For improving solubility, as with anhydrous soluble materials that tend to set when wet
5. For improving blending, since there is no migration of ingredients might occur during the drying of wet granulation

Disadvantages
1. It requires a specialized heavy-duty tablet press to form the slug 2. It does not permit uniform color distribution as can be achieved with wet granulation 3. A pressure roll press such as the Chilsonator cannot be used with insoluble drugs 4. The process tends to create more dust than wet granulation

(VI). Problems in Tablet Manufacture

1. Binding (binding in the die) Increase lubrication

Use more efficient lubrication

Improve method of addition of lubricant Increase moisture or regranulate Modify granulation: reduce granule size Increase punch-die clearance Taper dies Compress at lower temperature and.or humidity

2. Sticking ( filming or picking, some granules sticking to punch faces)

Decreasing moisture content of the granulation Change or decrease the lubricant Increase the proportion of binder in the granulation Add an adsorbentmicrocrystalline cellulose, silica gel, et al

Clean punch faces with 5% light mineral oil in isopropanol

Polish punch faces on lathe with jewelers rouge ( )or fine emery cloth () or chromium plate punches

3. Capping and Lamination

Remove some or all of the fines through a 100 to 200 mesh screen Increase or change lubricant Reduce or change lubricant Dry or moisten granulation, using moisture analysis to determine limits Improve granulating procedure Increase binder or wetting of the granulation

Taper dies 0.0005 to 0.002 inch, depending on diameter

Add dry binder Reduce upper punch by 0.0005 to 0.001 inch

4. Chipping and cracking

Replace or reface nicked or chipped punches Reset table press take-off

Improve granulation by increasing binder and/or by wetting of the granulation

Add dry binder or plasticizer such as PVP, pregelatinized starch, powdered acacia, and microcrystalline cellulose Polish punch tips Remove some or all fines

Reduce granule size

Reformulate to attempt to eliminate expansion of table 5. Tablet Expansion

(2) Package Development & Comparative Stability

The functions of a drug package Containment

Protection
Other Essential Functions

The package must provide some way to dispense the contents, either into another container or directly onto the hand or into the body.
Some provision must be made for reclosure of the package so the unused contents will not lose their potency or efficacy, become contaminated or represent a hazard to small children.

When the package contents are sterile, this sterility must be maintained, including the sterility of the unused remainder.

The package must present all the information about the drug that is required by law and good therapeutic practice.

The package should help sell over-the-counter (OTC) products without the need for intervention by a pharmacist.

Although most packages do not perform this function, packages which aid in compliance pay large dividends in reduced healthcare costs.

The package design must provide evidence of tampering for those products which are so regulated by the FDA. Generally, all OTC drugs fall into this category.

Packages for prescription drugs and certain OTC products must thwart access by young children.

Frequency of use of various containers

container % of total 1991 (Dollar Sales)
Plastic containers
Paperboard containers Blister packages

24.7
21.3 11.9

Labels and package inserts

Plastic closures Glass containers Metal containers Nonplastic closures Miscellaneous

11.1
10.8 7.1 4.0 3.4 5.7

Packaging Needs
Stability: moisture, oxygen, light Purity and Sterility: Packaging material not be a source of contamination. Packaging material must withstand the sterilization of manufacturing process Drug Physiology: A critical packaging need for certain route Solid Dosage Forms: Preventing moisture or oxygen pickup Liquids: No leakage; No contamination; Retention of sterility, transparency. Ointment: Means of convenient and sanitary Withstanding sterilization for ophthalmics

Packaging Guidelines
Parenteral Glass ampules and vials: The information of the manufacturers name, the glass type, a physical description of the container, its chemical resistance, its light transmission Compatibility with contents which includes leaching and/or migration tests, sampling plan and acceptance.

Plastic vials: The information of the manufacturers name, the plastic type, its composition, the method of manufacture, analytical controls; light transmission, certain USP tests, vapor transmission. Compatibility with contents which includes leaching and/or migration tests, a sampling plan and acceptance.

Nonparenteral
The guidelines for glass and plastic bottles are similar to glass and parenteral containers, but a description of the desiccant, if present.

Glass Type I: borosilicate glass, containing 80% silicon dioxide and 10% B2O3 with smaller amounts of Al2O3 and Na2O Type II: de-alkalized soda-lime glass with higher level of Na2O (13~17%) and CaO (5~11%) Type III: containing sodium and calcium oxide levels like Type II but contains more leachable oxides of other elements.

Advantages Impermeable all gases, excellent clarity, easy clean and sterilize with heat, inert material, variety of shapes, filling-friendly, good compresssional strength, hot filled

Disadvantages
Density2~2.5 g/cc, brittle character more expensive Metal Tinplate: tin coating to sheet steel Aluminum: 10 mils for rigid containers (1 mil= 1/1000 inch) 3-5 mils for semirigid foil containers 1 mil for blister construction 0.3 mils for foil in laminates

Plastics
Advantages light, 1-1.5 g/cc

manufacturing complex container

design freedom shatter-proof

crystal clear or totally opaque

heat sealing, readily printing inks less expensive Disadvantages gas permeability, not inert

Stress cracking in the presence of alcohols

Disadvantages

Gas permeability, not inert

Stress cracking in the presence of alcohols, organic acids, ethers and may oils Heat, sunlight and oxygen sensitive Poor conductors of electricity

Leaching additives
Plastic Materials

Polyethylene (PE), Polyvinyl chloride (PVC), Polypropylene (PP), Polyvinylidene chloride (PVDC), Polystyrene (PS), Fluorine-containing polymers, Polyurethane

Polyethylene (PE) High density polyethylene (HDPE) 0.95-0.97 Low density polyethylene (LDPE) 0.91-0.93

Property
Density g/cc Tensile Strength, kpsi

LDPE
0.91-0.925 1.2-2.5

HDPE
0.945-0.967 3.0-7.5

Tensile Modulus
1% Secant, kpsi Haze, % WVTR, g.mil/100 in2 day 100 F &90% RH 1.2 0.3-0.65 20-40 4-10 125 25-50

Fluorine-containing polymers
PTFE: polytetrafluoroethylene Teflon, used in drug packaging, as a liner for rubber stoppers. ACLAR: polymer of trichlorofluoroethylene, used in drug packaging as a laminate width PVC in blister packages.

Polyurethane Foamed polyurethane used for tablet bottle stuffing USP Package Designation

Well-closed container
Tight container Hermetic container

USP Package Designation Well-closed container Tight container Hermetic container Light resistant container Single unit container

Single dose container

Unit dose container Multiple dose container

Compatibility
Interaction of a drug and the package Reduction in drug availability or potency through sorption

Contamination as the formulation extract substances from the package

Breakdown of the package by deterioration of its strength, stiffness or barrier properties as the formulation chemically attacks the package Sorption can change product potency Leaching can cause pharmaceutical products to discolor precipitate, change pH, and became contaminated. Container modification can lead to container breakdown and product leakage.

(3). Process Development, Proposed Product Pilot Testing, Stability Studies, & Master Batch Documentation
Process Development, Proposed Product Pilot Testing example: Tablets

Solid-solid mixing, solid-liquid mixing, milling, or size reduction, drying, and compaction
Selection of the formulation components and equipment

Optimization of the efficiency of the unit process

Review of the formula: each ingredient and its contribution need be understood Raw materials: active ingredientssupplier Relevant processing equipment: relevant to production size Production rates: consideration of the future market requirements

Process Evaluation: Order of addition of components, including adjustment of their amounts Mixing speed, Mixing time Rate of addition of granulation agents, solvents, solutions of drugs, slurries Heating and cooling rates Filter sizes (liquids) Screen sizes (solids) Drying temperatures, Drying time

Stability Studies, Master Batch Documentation Development