Pharmaceutical Pre-Formulation

Introduction to pre-formulation - the first learning phase is known as pre-formulation: gives 'ball-park' figures on which to base future decisions. - at this stage the potential active drug is known as New Chemical Entity (NCE). TESTS SLIDE 4 What are the two fundamental properties that are mandatory for a new compound? Intrinsic solubility (Co) and dissolution constant (pKa). Spectrometry - first step in pre-formulation is to develop a simple quantitative analytical technique. - most drugs absorb light in the UV regions since they are generally aromatic and contain double bonds. - the amount of light absorbed by a drug is proportional to its concentration. Beer Lambert Law. Aqueous Solubility - solubility dictates the ease wit which formulations of solutions can be prepared. - pKa allows the informed to use pH to maintain solubility and allow the appropriate use of salts. - Kaplan suggested that unless a compound has an aqueous solubility in excess of 1% w/v over the pH range 1-7 at 37 degree, potential bio-absorption problems my arise. - Similarly if the intrinsic dissolution rate > 1mg/cm2min then absorption will be unimpeded. (<0.1mg/cm2min were likely to give dissolution rate limited absorption - under sink conditions, dissolution rates and solubility can be assumed to be proportional. - a solubility less than 0.1%w/v indicates the need for a salt. 1/5 Intrinsic Solubility (Co) - when the purity of the drug sample can be assured, the solubility value obtained in acid for a weak acid or alkaline for a weak base can be assumed to be the intrinsic solubility (Co) ie the solubility of the NCE when completely unionised. - ideally solubility should be measured at two temperatures: 4 degrees: to ensure physical and chemical stability on extended short term storage. The maximum density of water occurs at 4 degrees and this leads to a minimum aqueous solubility. 37 degrees: to support biopharmaceutical evaluation. Solubility and purity absolute purity is often in doubt with pre-formulation samples, impurities can either increase or decrease the NCE's solubility. A reasonable accurate method of accuracy of intrinsic solubility can be made by the use of a phase diagram, with varying the amount of drug to the amount of solvent. pKa for solubility data FORMULAS SLIDE 11 some molecules do not form salts, such as those which do not dissociate when added to water (steroids or alcohols). Salts Salts and the stomach in some cases, salts prepared from strong acids (eg hydrochloride) or bases (eg sodium, potassium) are freely soluble but very hygroscopic. A weakly basic drug will have a high dissolution in the stomach but as it moves down the gastrointestinal tract, the pH rises and dissolution and solubility will fall. The opposite is true for a weak acid. 2/5 Paradoxically, as dissolution rate increases, the bioabsorption of the molecule falls because the drug is ionised. cont. Melting Point different salts of a drug rarely change its fundamental pharmacology but do change its physiochemical properties. - such changes can effect the intensity of drug response. - each NCP is examined to choose the most appropriate salt form with each slat form requiring separate preformulation screening. - simple test which can provide information regarding the thermal properties of the NCP including potential stability and solubility. - melting point and solubility are related through their latent heat of fusion which is the amount of heat generated during melting or fusion. A strong crystal lattice leads to a high melting point and high heat of fusion. Capillary Melting Hot Stage Microscopy Differential Scanning Calorimetry (DSC) or thermal analysis (DTA). What is Differential Thermal Analysis (DTA)? Measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate Measures the amount of energy required to keep the sample at the same temperWhat is Differential Scanning Calorime- ature as a reference ie it measures the try? enthalpy of transition. The major concern in pre-formulation is 3/5 polymorphism and the measurement of melting point and other phase changes are primary diagnostic tool. Assay Development - important for indicating suitable stability. They include: 1) spectrometry 2) Thin layer chromatography 3) High performance liquid chromatography (HPLC)- normal and reverse phase HPLC its great flexibility of choice in mobile Why is HPLC the method of choice for phase, the increasing number of availpre-formulation stability studies? able stationary phases and inherent sensitivity. Drug and Product Stability - wherever possible, commercial pharmaceutical products have a shelf life of 3 years. Stability testing is important at the pre-formulation: 1) provides evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. 2) advises on formulation approaches, indicated specific excipients, protective additives and packaging that are likely to improve the integrity of the drug. 3) establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions 4) physical, chemical or microbiological changes might impact the efficiency and security of the final product. 4/5 - volatility - loss or uptake of solvent deliquescent/hygroscopic/efflorescent - polymorphism - changes in heterogenous systems Physical Instability (creams, emulsions, suspensions etc.) - denaturation (bio-molecules) - ionisation and solubility; pH dependancy - absorbance/partitioning (packing material) - hydrolysis - oxidation - elimination: decarboxylation, dehydration - racemisation and isomerisation Chemical Instability - rearrangement: photochemical or acid catalysed - photodegradation - incompatibilities: solvent/drug, drug/drug, packing materials) 1) Basic crystallography: to determine crystal morphology (structure and habit), polymorphism and solvates. Conditions during the crystallisation process will contribute to changes in crystal habit. Crystal habit can be modified by; excesWhat are the two main application of mi- sive supersaturation, cooling rate and agitation, change of crystallising solvent croscopy in pre-formulation? and by the addition of cosolvents. Particle size analysis: dissolution is directly proportional to Surface Area (Noyes Whitney). Particle size is measured by a number of different techniques. SLIDES 24-27 BULK DENSITY AND ANGLE OF REPOSE. 5/5