Preformulation Studies VL
Preformulation Studies VL
Preformulation Studies VL
Preformulation
What does it convey?
PREFORMULATION
FORMULATION
SCIENTIFIC SUPPORT Organic
Medicinal
Biochemistry
CLINICAL
Preformulation begins or shall be updated immediately after the synthesis and initial toxicity screening of a new drug when a newly synthesised drug shows pharmacological evidence that requires further evaluation in man when formulation and dosage form changes are required Characterization of all Preformulation bulk lots is necessary to avoid misleading predictions of stability or solubility, which depend on particular crystalline form.
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These studies should focus on: Physicochemical properties that affect drug performance and development of efficacious dosage form. These properties may provide: Support the need for Molecular modifications A rationale for Formulation Design
Preformulation
Preformulation investigations are designed to deliver all necessary data (especially physicochemical, Physiomechanical and biopharmaceutical properties of drug substances, excipients and packaging materials) which may Influence
formulation design method of manufacture of drug substance and drug product pharmacokinetic/biopharmaceutic properties of the resulting product packaging of the product
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Direct Benefit
Gives directions for development of formulation in choice of dosage form, excipients, composition, physical structure... Helps in adjustment of pharmacokinetic and biopharmaceutical properties Support for process development of drug substance (yield, filtration...) Support for PAT (Process Analytical Technology) (critical process parameters...) Produce necessary and useful data for development of analytical methods.
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Where to begin?
Desk work. Active substance Additives Process conditions Analytical means
Protocols..
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I-
To Generate the physical and chemical properties information that will assist the formulator in developing:
*Stable *Safe *Effective Dosage Forms that can be mass produced with: Maximum Bioavailability (Support Dosage Form Design)
II- To provide an initial working model of behaviour of dosage form in vitro and in vivo III- To establish the compatibility of the drug with common excipients. IV- To establish the kinetic rate profile of the drug. V- To Provide a scientific data that support the dosage form design and evaluation of the product efficacy, stability and bioavailability
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Evaluation Phase
Calculation/Prediction in silico of many of the important physicochemical characteristics of NCE solubility polymorphism morphology of the particles acute toxicity intestinal permeation
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Evaluation Phase
Literature search of similar or related compounds to provide an understanding of the degradation process any adverse conditions relevant to the drug bioavailability pharmacokinetics and formulation of similar or related compounds
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Parenteral Dosage Forms Injection site precipitation Pain upon injection Toxicity of new excipients Effect of excipients on crystallization/nucleation
Suspensions Effect of processing and formulation on the physical and chemical stability Effect of excipients on crystallization/nucleation
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API
Study what?
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Index of studies
Stress Testing of API Impact of Impurities on API Specifications Pre-Formulation Investigations Solid State Degradation & Stability Assessment Role of Excipients in API Instability Hydrolysis Oxidation Photolysis API Solubility/Solution-state Stability Assessment Selection of API & Drug Product Processing Methods Degradation Issues for Combination Products Role of API Processing in Product Instability
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Analytical Preformulation
Know what you start with..
Identity NMR, UV, TLC, DSC Purity Moisture Content, Impurity Profile, DSC, Heavy element, Inorganic elements. Assay UV, HPLC
Quality
Appearance, Odour, pH of Slurry, Melting Point
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To facilitate development of a stability indicating analytical method, e.g. HPLC To aid in development of the first API specification To understand the degradation pathways of the API to facilitate rational product development To screen for possible formation of potential genotoxins
Initially performed over a short period of time (28days) using accelerated or stress conditions (so that reactions proceed more rapidly); target ~10% degradation.
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pH 1-9 in buffered media with peroxide (and/or free radical initiator) Light irradiation
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The allowable level of any given impurity or impurities that are permitted in API/drug product, without explicit non-clinical safety testing, are defined by ICH Q3A/B.
The amounts of impurities that are allowable are based on the total daily intake of the drug product.
There are separate limits (or thresholds) for reporting, identification and qualification of API impurities.
The reporting threshold is defined as the level that must be reported to regulatory agencies to alert them to the presence of a specified impurity.
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The identification threshold is defined as the level that requires analytical identification of a specified impurity. Finally, the qualification threshold is defined as the level where the specified impurity must be subjected to non-clinical toxicological testing to demonstrate safety. Threshold limits are defined as a percentage of the total daily intake (TDI) of the drug product, or in absolute terms as the total allowable amount, whichever is lower.
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Reporting
0.1%TDI 0.05%TDI
Identication
Qualification
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Polymorphism
What is it?
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Internal Structure
Molecular Ordering
Crystalline
Ordered
Polymorphism
Polymorphism is a solid state property of organic
molecule which can be obtained in more than one distinct crystal form. Polymorphism may also include solvation or hydration products and amorphous forms enantiotropic one polymorph can be reversibly changed
into another one by varying the temperature or pressure monotropic the change between the two forms is irreversible
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These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability.
Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.
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Characterization of polymorphs
X- Ray Diffraction Microscopy, Thermal analysis Differential scanning calorimetry, thermal gravimetric analysis, and hot-stage microscopy Spectroscopy Infrared [IR], Raman, solid-state nuclear magnetic resonance [ssNMR]
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Trees 1. and 2. consider whether polymorphism is exhibited by the drug substance, and whether the different polymorphic forms can affect performance of the drug product.
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Trees 1. and 2. consider whether polymorphism is exhibited by the drug substance, and whether the different polymorphic forms can affect performance of the drug product.
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H3C
Case history:
ABT-538 discovered Launch of semi-solid capsule/polymorph I Polymorph II appears, <50% solubility Product pulled from the market 1998 - 1999 Massive effort to reformulate the product 1999 Reformulated softgel capsule launched 1992 1996 1998
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mp 122 C
mp 125 C
mp 80 C
mp 97 C
mp 116 C
Launch in 1996 Launch in 1996 Summer of 1998 Summer of 1998 Morissette et al. PNAS 100, (2003). TransForm 2002 6 week effort 2002 5 forms found
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API Processing
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With some materials, ball milling causes irregularity, surface faults and imperfections in crystals. The degree of crystal damage can be directly correlated with the energy of the milling process.
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API related..
Preformulation studies are an important foundation tool early in the development of both API and drug products. They influence.
Selection of the drug candidate itself Selection of formulation components API & drug product manufacturing processes Determination of the most appropriate container closure system Development of analytical methods Assignment of API retest periods The synthetic route of the API Toxicological strategy
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Preformulation Steps
Solubility (aqueous, pKa, log P, log D) Molecular optimization (salt, hydrate, solvate, new analogs,) Crystal Engineering (polymorph, habit, size, surface characteristics) Crystal structure determination Biopharmaceutical classification (BCS) (solubility, dissolution, absorption)
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Preformulation Steps
Complete Physical and Chemical Characterization Drug stability evaluation (physical, chemical, solution phase, solid phase, ) Compatibility analyses (drug substance, excipient, packaging materials) Technical characterization (Flowability, Compactability, ...
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Solubility
Solubility may be defined as the maximum concentration of a substance that may be completely dissolved in a given solvent at a given temperature and pressure. Drug candidates are becoming more lipophilic and poorly soluble A Market Survey of 257 Marketed Drug and their liphophilicity
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definition
The USP/NF generally expresses the solubility in terms of the volume of solvent required to dissolve 1 gram of the drug at a specified temperature (eg. 1 g ASA in 300 ml H2O, 5 ml ethanol at 25C).
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SATURATION SOLUBILITY
SATURATION SOLUBILITY is understood as a maximum amount of solute that dissolves in a solvent at equilibrium. Equilibrium is a state where reactants and products reach a balance - no more solute can be dissolved in the solvent in the set conditions (temerature, pressure). Such a solution is called a saturated solution.
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Solubility parameters
Descriptive term Very Soluble Freely Soluble Soluble Sparingly soluble Slightly soluble Parts of solvent needed for 1 part of solute <1 1 to 10
10 to 30
30 to 100 100 to 1000 1000 to 10,000
> 10,000
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Dissolution
Dissolution rate for poorly soluble compounds may often be the rate limiting step to absorption Examples of drugs with dissolution rate limited absorption: - Digoxin - Penicillin V - Phenytoin
- Quinidine - Tetracyclines
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Buffers
Co-solvents (GRAS approved) Additives/complexes -surfactants, polymers, cyclodextrins Lipid-based systems (solutions, emulsions) Solid-state modification (particle size reduction, salt formation, solid-state stabilisation of the amorphous state)
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Particle Size
Important?
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Micromeritics
Micromeritics is the science of particle sizes, particle shapes, size distributions, porosity, density and surface areas.
Methods Microscopy Sieving Laser diffraction Others: Sedimentation, Coulter counter etc.
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Microscopy
Advantages For Small sample Direct technique Particle shape can be determined Image analysis system available It can be caliberated Disadvantages Statistically poor Problem with broad size distribution Not very fast Sample preparation Two dimensional analysis
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Sieve Analysis
Advantages Determining samples having broad size distribution. Easy to operate Calibrated sieves Disadvantages Inaccuracy increases in the size of < 75 um. Large sample size.
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Sieve Analysis
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Laser Diffraction
Advantages: Precise Fast Analysis. Small sample amount Well automated and statistically good method Accepted by various regulatory authorities. Disadvantages: Needs expertise. Expensive. Sample is destroyed.
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Laser Diffraction
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Dissolution profiles in USP apparatus 2 at 50 rpm and pH 4.5 for product produced with different particle size of the API
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Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market
USP Type II / 0.01N HCl 50 RPM / 900 ml 120
% Drug Dissolved
100 80 60 40 20 0
F2
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Flow
How important?
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Flowability
Primary forces at work: Friction Particle size and shape Cohesion Moisture, fats, oils Molecular forces, electrostatic forces Environmental Temperature, pressure, time Physical Bin angle, aperture diameter Wall conditions
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Flowability methods
Flowing time
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Angle of Repose
= 2H tan 1 D H = Height of cone [4.1 cm] D = Base of cone [9.8 cm] = Angle of repose 2 x 4.1 tan 1 = 39.93 o 9.8
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Angle of repose
Flow property Excellent Good Fair-aid not needed Passable- may hang up/ block Poor- must agitate vibrate Very Poor Very, very poor Angle of repose {degrees} 25 - 30 31 35 36 - 40 41 - 45 46 - 55 56 - 65 > 66
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Carr Index
Carr Index =
Carr Index (%) 5-15 12-16 18-21 23-35 33-38 > 40
Tapped Density- Bulk Density X 100 Tapped Density
Type of Flow Excellent Good Fair to Passable* Poor* Very poor Extremely Poor
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Hygroscopicity
Environment control
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Slightly hygroscopic: Increase in mass is less than 2 percent m/m and equal to or greater than 0.2 percent m/m. Hygroscopic: Increase in mass is less than 15 percent m/m and equal to or greater than 0.2 percent m/m. Very hygroscopic: Increase in mass is equal to or greater than 15 percent m/m. Deliquescent: Sufficient water is absorbed to form a liquid.
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Corrosive potential
Affects which stage?
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Corrosivity
Personnel safety Equipment Pack Scale of operations Cleaning process Handling procedures
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What is covered ?
Bulk properties crystallinity and polymorphism Hygroscopicity (water adsorption) Fine Particle Characterization (particle size, shape, and surface area) powder flow Properties (Bulk Density, angle of repose, compressibility)
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Ionization Constant
The unionized species are more lipid-soluble and hence more readily absorbed. The gi absorption of weakly acidic or basic drugs is related to the fraction of unionized drug in solution. Factors affecting absorption: - pH at the site of absorption - Ionization constant - Lipid solubility of unionized species pH-partition theory 94
What is covered?
solubility analysis Intrinsic Solubility ionization Constant pH solubility profile partition coefficients Salts Solvents Dissolution
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Dissolution testing
Dissolution testing is used for the selection of the formulation and comparison of the dissolution profiles with that of the innovator product and clinical batches. This should be a basic strategy in pharmaceutical development to maximize the chances of bioequivalence. Limits should be set for each API in fixed-dose FPs. The dissolution method should be incorporated into the stability and quality control programs. Multipoint dissolution profiles of both the test and the reference FPs should be compared.
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2. 3. 4.
Stability Analysis..
Serves two purposes: To evaluate the specificity of the stability indicating method, e.g. LC To understand the degradation pathways of the API to facilitate rational product development i.e.Hydrolysis, Oxidation, Photolysis and the role of pH
Wherever possible, commercial pharmaceutical products should have shelf-life of Three years. The potency should not fall below 90 or 95% under the recommended storage conditions and the product should still look and perform as it did when first manufactured.
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Testing period*
3 months 3 months according to ICH
* 3 months or 5-15% degradation, whatever comes first ** For API1-API2, or API-excipient, or FPP (finished pharmaceutical product) without packing material, typically a thin layer of material is spread in a Petri dish. Open storage is recommended, if possible.
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Testing period*
2 weeks 2 weeks 2 weeks 24 hours
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Arrhenius Equation
Thermal effects are superimposed on all four chemical processes mentioned above. Typically a 10C increase produces a two- to five fold increase in the rate of reaction. Example. Storing b-lactam penicillins in a refrigerator reduces the hydrolysis rate by 90% of that at room temperature. K = A e Ea/RT or log K = log A (Ea/2.303R)/T. Plotting the rate of reaction (K) against 1/T K allows the calculation of rate at any temperature (Ea, activation energy; R, gas constant), and therefore a prediction of shelf-life (t90, time to 90% potency). This forms the basis of many accelerated stability tests!
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PHOTOSTABILITY
Many pharmaceutical drug molecules are known to be
sensitive to light and degrade chemically under light exposure. During the development we have to evaluate this risk and how we can stabilise a potential photo-labile drug with packaging material, films and/or colorants. This evaluation of the drug molecule can be done by Isothermal Microcalorimetry (IMC) in real time. Photosensitivity of molecules is often studied in solutions, and the changes in concentrations have been examined by chromatography and spectrophotometry. Discoloration of powders has been examined by colorimetry.
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Photostability studies
A systematic approach to photostability testing is recommended covering, as appropriate, studies such as: (i) Tests on the drug substance; (ii) Tests on the exposed drug product outside of the immediate pack; and if necessary, (iii) Tests on the drug product in the immediate pack; and if necessary, (iv) Tests on the drug product in the marketing pack.
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Photostability studies
Light Sources: Option 1 Dual output light sources, such as D65/ID65 Simulates artificial day light fluorescent lamp Use Xenon or Metal Halide Option 2 Tandem exposure to single light source types Cool white fluorescent lamp + near UV fluorescent lamp (320-400 nm) Accumulate exposure under one, then the other
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pharmaceutical Substances
Incompatibility is an undesirable interaction between two or more substances
drug drug, drug excipient, drug packing material, excipient packing material
Interaction can be chemical, physical or both Physical/chemical stability data of pure components obtained at the same time
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Advantages
Prerequisite of the stable and effective formulation Saves time - facilitate formulation process (exclude high-risk excipients) Lowers risk - support process and packaging development decisions Saves money - minimize the number of needless, formal (expensive) stability studies
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Methods
Applied procedures
Desktop working Traditional way Microcalorimetric way Application of Phys. analytical methods X-Ray Powder Diffraction, XRPD Differential Scanning Calorimetry, DSC Isothermal Microcalorimetry, IMC Inverse Gas Chromatography, IGC Chemical methods (HPLC, TLC,)
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Desktop Working
PROCEDURE molecular formula of active substance and potential excipient are compared to each others potential interaction points are listed molecule modeler typically hunts compatible molecules with target molecule as a purpose getting strong interaction with the binding site of the target molecule pharmaceutical formulator decides on the basis of the list of excipients which have a minimum number of potential interaction points
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Traditional Procedure
One option Binary Mix Compatibility Testing: samples or of drug and excipients are intimately mixed (1:1), but other mixtures used as well samples can be either powder blends or compressed discs one set of samples are moistened and sealed into ampoules to prevent moisture loss study design stored under room and accelerated conditions at least 1 week in accelerated conditions 40CRH75% or 60 C RH75% 1-3 month in room conditions (25CRH60%) analysed at various time points using HPLC, DSC and TGA (NIR, Raman, XRD,) and visually 113
Traditional Procedure
However, the binary mix approach takes time and resources and.it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi-component prototype formulation.
An alternative is to test prototype formulations. The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend. Platform prototypes can be used for specific dosage forms, e.g. DC vs. wet granulation in tablets There is better representation of likely formulation chemical and physical stability
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Drug excipient.
Can apply statistical models (e.g. 2n factorial design) to determine the chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture.
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Microcalorimetric Procedure
Most chemical or physical processes are due to changes in free energy and are usually accompanied by heat change.
ISOTHERMAL MICROCALORIMETRY (IMC) can monitor these changes ISOTHERMAL MICROCALORIMETRY (IMC) is exceptionally sensitive technique to see any reactions in the sample: - It has been estimated that a change that would take more than 200 years to run to completion could be easily detected with IMC - temperature difference sample versus reference < 10-6 C detectable - degradation rate 0.01%/annum detectable Non-specific method - for fully interpretation of the data it is necessary to investigate the origin of the thermal events by additional methods
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Method
about 1 gram of sample into the specific sample ampoule heat flow curves of pure substances are compared to those of the binary mixtures incompatibility is revealed if the features of the heat flow curve of the mixture doesnt resemble the sum curve of the components of the binary mixture studied.
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Microcalorimetric Example
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XRD Application/Methods
X-Ray Powder Diffraction powerful equipment to evaluate solid state properties
- polymorphism - solvation state (solvates, hydrates) - Crystallinity useful method to reveal any other phase transition or solid state impurities of the samples. non-ambient XRD can give valuable supporting data for stability prediction - humidity and temperature can be controlled
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XRD Example
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Excipient Compatibility
API: EXC EXC:EXC API: PACK
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Excipients:API Interaction
Whereas excipients are usually biologically inactive, the same cannot be said from a chemical perspective. Excipients, and any impurities present, can stabilise and/or destabilise drug products.
Considerations for the formulation scientist: the chemical structure of the API the type of delivery system required the proposed manufacturing process
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Excipients:API Interaction
expert systems; predictive tools desired delivery characteristics of dosage form knowledge of potential mechanisms of degradation, e.g. Maillard reaction Prior development experience
The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quickly as possible, real and possible interactions between potential formulation excipients and the API. This is an important risk reduction exercise early 126 in formulation development.
In the typical drug/excipient compatibility testing program, binary (1:1 or customised) powder mixes are prepared by triturating API with the individual excipients. These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions and analysed by stability-indicating methodology, e.g. HPLC. (The water slurry approach allows the pH of the drug-excipient blend 127 and the role of moisture to be investigated.)
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However, the binary mix approach takes time and resources and it is well known that the chemical compatibility of an API in a binary mixture may differ completely from a multi-component prototype formulation. An alternative is to test prototype formulations. The amount of API in the blend can be modified according to the anticipated drug-excipient ratio in the final compression blend.
Platform prototypes can be used for specific dosage forms, e.g. DC vs. wet gran tablets
There is better representation of likely formulation chemical and physical stability However, this is a more complex system to interpret
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Drug-excipient interactions can be studied using both approaches in a complementary fashion. The first tier approach is to conduct short-term (1-3m) stability studies using generic prototype formulations under stressed conditions, with binary systems as diagnostic back-up: Chemical stability measured by chromatographic methods Physical stability measured by microscopic, particle analysis, in vitro dissolution methods, etc. The idea is to diagnose any observed incompatibility from the prototype formulation work then hopefully identify the culprit excipients from the binary mix data. Hopefully, a prototype formulation can then be taken forward as a foundation for product 130 development.
Can apply statistical models (e.g. 2n factorial design) to determine the chemical interactions in more complex systems such as prototype formulations, with a view towards establishing which excipients cause incompatibility within a given mixture.
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EXCIPIENTS - STARCH
All starches are hygroscopic and rapidly absorb atmospheric moisture. Approximate equilibrium moisture content values at 50% relative humidity are: 11% FOR MAIZE (CORN) STARCH,
18% FOR POTATO STARCH, 14% FOR RICE STARCH, AND 13% FOR WHEAT STARCH.
Between 30-80% relative humidity, corn starch is the least hygroscopic starch and potato starch is the most hygroscopic starch.
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Excipients play a key role in oxidation; either as a primary source of oxidants, trace amounts of metals, or other contaminants.
E.g. Peroxides are a very common impurity in many excipients, particularly polymeric excipients. They are used as initiators in polymerisation reactions, but are difficult to remove.
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More examples.
Lactose can react with primary amines. Silicone dioxide acts as Lewis acid
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Conclusion
Preformulation Study is Major tool for pharmaceutical product Development - it saves time as well as cost for development of Dosage form.
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Pharmaceutical Preformulation and Formulation by Mark Gibson The theory and practice of Industrial pharmacy by Lachman Pharmaceutics by Aulton Handbook of Preformulation by S. Niazi
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Thank you!
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