preformulationNFormulationOfPharmaceuticals .pdf

Preformulation & Formulation of Pharmaceuticals Yussif Saaka BPharm, MSc., Ph.D., MPSGH Department of Pharmaceutics [email protected] SOPH 331 PHARMACEUTICAL TECHNOLOGY II UNIVERSITY OF HEALTH AND ALLIED SCIE...

Preformulation & Formulation of Pharmaceuticals Yussif Saaka BPharm, MSc., Ph.D., MPSGH Department of Pharmaceutics [email protected] SOPH 331 PHARMACEUTICAL TECHNOLOGY II UNIVERSITY OF HEALTH AND ALLIED SCIENCES School of Pharmacy  Objectives To understand: o physico-chemical properties related to preformulation. o Assay design o Spectroscopy o Solubility o Melting point o Stability o Microscopy o Powder flow o Compression properties 2  Introduction The Pharmaceutical market is large: o $ 856 Billion in 2010 (4.1 % growth from 2009) o vast array of compounds with the potential to become drug substances. o however only 1 in 5 – 10,000 will be successfully developed into a marketed drug product o estimated development cost = $ 1.8 Billion o Over 70 % of promising candidates never generate sufficient sales to recoup their development costs. o Proper physical and chemical drug-characterization is KEY!!! 3  Introduction Preformulation: o the investigation of physical and chemical properties of a drug substance, often newly discovered, alone or in combination with excipient. o the formulator obtains useful information on the _________ of potential drug candidates § identity q chemical identity using UV, NMR, IR, TLC, DSC § purity q moisture content, Inorganic elements, heavy metals, organic impurities § assay § quality q appearance, odour, solution colour, pH of slurry (saturated solution) and melting point 4  Preformulation Common assay tests include: o Assay § Structural elucidation § Solubility § Melting point § Stability § Microscopy o Powder flow o Compression properties 5  Assay Design Assay design: o a formulator most often requires only knowledge of solubility and the development of a suitable assay in order for development to commence. o An ideal assay should: § require minimum amounts of sample § allow determination of multiple parameters § be applicable to a range of compounds. 6  Assay Design Below is a list of molecular properties to be measured during preformulation, in chronological order, and the assays that may be used to quantify them. Property: Solubility (aqueous and non-aqueous) Assay: UV Sample requirement: Chromophore Property: pKa Assay: UV or potentiometric titration Sample requirement: Chromophore or acid/base group Property: LogP Assay: UV, TLC, HPLC Sample requirement: Chromophore *What is the difference between LogP and LogD? 7  Assay Design § Property: Hygroscopicity Assay: DVS, TGA Sample requirement: None § Property: Stability (hydrolysis, photolysis, oxidation) Assay: HPLC, suitable storage conditions Sample requirement: None The properties above provide information on molecular structure. o Once known, further macroscopic (or bulk) properties of the drug candidate can be measured. 8  Spectroscopy UV spectrophotometry is popular because: o of cost o of availability o small quantities of material are used o majority of drug substances contain at least one functional group that absorbs in the ultraviolet (UV) region (190 – 390 nm) § these functional groups are known as chromophores Chromophore 𝜆!"# (nm) Molar absorption (𝜀) Benzene 184 46,700 Naphthalene 220 112,000 Anthracene 252 199,000 Ethylene 190 8,000 Ketone 195 1,000 9  Spectroscopy UV spectrophotometry: o chromophores: § excitation of a molecule in solution reduces the amount of light passing through the solution. § If the original light intensity is 𝐼$ and the amount of light passing through the sample (the transmitted light) is 𝐼, then the amount of light absorbed is directly proportional to the concentration of the solute, 𝐶 and the path length, 𝑙 𝐼 Absorbance = log = 𝜀𝐶𝑙 𝐼$ § Higher values of molar absorption coefficient, 𝜀 = greater absorbance. 10  Spectroscopy UV spectrophotometry: o In Pharmacy, 𝐶 = % w/v § so 𝜀 = specific absorption coefficient, 𝐴44 % 56 § i.e. the absorbance of a 1 %w/v solution in a 1 cm path length UV cuvette: 𝐼 Absorbance = log = 𝐴44 % 56𝐶𝑙 𝐼$ 11  Solubility Generally, o a drug substance must be in solution in order to be absorbed by the body. § Yet many drugs are formulated in the solid state. This is often because of stability and ease of manufacture and transportation. o Understanding the solid-state properties: § provides the foundation upon which to develop the dosage form o However, understanding the following properties are critical in predicting and optimising drug product performance: § The process by which the drug transitions from the solid state into solution. § The equilibrium concentration (thermodynamic solubility)? § Maximum concentration (kinetic solubility)? *Find out differences between thermodynamic and kinetic solubility. 12  Solubility BCS: o considers solubility and intestinal permeability o defined as the ratio of drug absorbed through the GI tract following oral administration to drug administered intravenously. o Highly soluble drug substances: § the highest dose strength available is dissolvable in < 250 mL of water over a pH range 1 – 7.5 o Highly permeable drugs: o the extent of absorption in humans is greater than 90 %, based on a mass– balance analysis or in comparison to an intravenously administered dose. 13  Solubility BCS: o Solubility improvement is thus one development strategy for enhancing oral bioavailability of BCS class 2 and 4 drugs. o US Food and Drug Administration (FDA) permits a BCS biowaiver for immediate release BCS class 1 drug products: § In vitro dissolution data are sufficient and there is no need for human in vivo data BCS Class Solubility Permeability 1 High High 2 Low High 3 High Low 4 Low Low 14  Solubility USP and PhEur : o High solubility does not particularly indicate fast dissolution. § Since solubility is a position of equilibrium and dissolution is the rate at which equilibrium is established. Parts solvent to 1 Solubility range Descriptive Term part solute (mgmL-1) Very soluble 1000 Freely soluble 1 – 10 100 – 1,000 Soluble 10 – 30 33 – 100 Sparingly soluble 30 – 100 10 – 33 Slightly soluble 100 – 1,000 1 – 10 Very slightly soluble 1,000 – 10,000 0.1 – 1 Practically insoluble > 10,000 < 0.1 15  Solubility Measurement of solubility can be challenging: o if the compound dissolves to a very low extent and/or undergoes hydrolysis. o because in preformulation, small quantities (< 50 mg) of a drug substance may exist and neither its purity nor polymorphic form may be assured. Initial formulations, used for obtaining toxicity and bioavailability data in animal models: o need to be liquids for gavage or intravenous delivery and solubility greater than 1 mgmL-1. 16  Solubility For the drug product, assuming oral delivery in a solid form: o solubility above 10 mgmL-1 is preferable o These limits may be reduced if the drug substance is highly potent. For solubility < 1 mgmL-1: o Salt formation should be considered o Novel dosage form design may be required if salt formation is not applicable. § Note that the simplest, most robust dosage forms have the greatest chance of reaching the market. 17  Melting Point Melting point: o is used to study polymorphism, crystalline solubility and purity. o Useful because: § the limited quantities of drug powder during preformulation often precludes accurate solubility determinations. § thermal analysis is rapid and will discriminate 0.002 mole % of impurity. o Melting point is measured using the following techniques: § Capillary melting § Hot stage microscopy § Differential scanning calorimetry or thermal analysis (DSC or DTA). 18  Melting Point Polymorph: o a solid material with at least two different molecular arrangements that give distinct crystal species. o The highest-melting species is the least soluble and generally the most stable. § Other polymorphs are metastable and convert to the stable form. o Melting point vs solubility: § related via the latent heat of fusion (i.e. the amount of heat generated during melting or fusion). § A crystal with weak bonds = ↓ melting point and ↓ heat of fusion whilst strong crystal lattice = ↑ melting point and ↑ heat of fusion. § Solubility requires the disruption of crystal structure to allow molecular dispersion in the solvent, it is also influenced by intermolecular forces. 19  Stability Stability: o during preformulation, stability assessment is focused almost entirely on the properties of the drug substance itself, rather than the formulated drug product. o determining the stability profile of a drug substance or drug product with respect to light, temperature and humidity is central to successful development. o If multiple solid-state forms have been identified, the physical stability of the form selected for development should be investigated. § Stability in this context may refer to conversion rates to another physical form or to a change in structure o The allowed degradation limit is drug substance-dependent. § However, the lowest acceptable level of potency is 90 % of the label claim. 20  Stability Since time is limited during preformulation, o stability assessment at this stage involves challenging the compound (possibly in combination with likely excipients) by exposure to a range of environmental stresses o These stresses are often in excess of those that would normally be experienced. Stability testing protocols: o are defined in the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Guidelines Q1A(R2) o comprise long-term, intermediate, accelerated and stress conditions. 21  Stability Long-term storage: o The conditions under which the drug substance (and drug product) will be stored. Typically 25 ± 2 ℃ and 60 ± 5 % RH. At least 12 months data required for regulatory approval. Intermediate storage: o Typically 30 ± 2 ℃ and 65 ± 5 % RH. These conditions may also be selected for long-term storage, in which case no intermediate conditions are needed. At least 6 months data required for regulatory approval. Accelerated stability: o Typically 40 ± 2 ℃ and 75 ± 5 % RH. At least 6 months data required for regulatory approval. 22  Stability Stress conditions: o carried out as a function of temperature (in 10 ℃ increments and at higher conditions than those used for accelerated stability assessment). o The effect on oxidation and photolysis should be studied where appropriate, as should the extent of hydrolysis across a range of solution pH. Since storage conditions vary around the world, four climatic zones are defined by the ICH: I. Temperate II. Subtropical and mediterranean III. Hot and dry IV. a) Hot and humid, b) Hot and very humid 23  Stability The principal causes of chemical degradation are: o hydrolysis (or solvolysis) § often catalysed in acidic or basic conditions. § A pH-stability profile is useful in identifying hydrolysis mechanisms. § Solvolysis is the same process as hydrolysis but the reactant is a solvent other than water (e.g. methanolysis = methanol). § Generally, if the degradation products are more polar than the parent molecule then addition of a less polar solvent will increase stability § If the drug substance and any degradants are nonpolar, such as the steroids, then there will be no change in stability with polarity = so any (physiologically acceptable) solvent may be added to increase solubility without affecting stability 24  Stability The principal causes of chemical degradation are: o oxidation § any reaction where the oxidation state of the reacting molecule is increased (i.e., it loses at least one electron). § oxidising agents gain at least one electron and are reduced, forming free radicals. § Reactions with oxygen are of the greatest interest, since it is abundant in the environment § Examples of drugs that are susceptible to auto-oxidation include adrenaline, ascorbic acid, heparin, hydrocortisone, morphine, the penicillins, and the tetracyclines. § Oxidation causes a loss of potency, discolouration and the development of an unpleasant taste. 25  Stability The principal causes of chemical degradation are: o photolysis § During preformulation, photostability testing may be performed on a single batch of drug substance under stress conditions. § Energy may be absorbed by a drug substance, transferred to other molecules or emitted at a different frequency, resulting in possible degradation and/or an increase in temperature. § Light energy may also promote oxidation and hydrolysis, so photostability testing in solution is as important as testing in the solid-state. § Since light energy is inversely proportional to wavelength, UV frequencies generally cause more degradation than visible frequencies. § Note: Plain glass absorbs more than 80 % in the 290–320 nm region, while amber glass increases absorption to nearly 95 %. o Find out: § techniques for drug stabilization. 26  Microscopy Microscopy: o most Pharmaceutical powders are in the 1 – 3000 𝜇m range o Formulation of nanomedicines is becoming an increasingly popular strategy. o The efficacy of many pulmonary devices is also critically dependent upon particle size, with powders needing to be in the 2–5 𝜇m range for effective pulmonary delivery. In preformulation, o light microscopy and electron microscopy are the most common instruments used to characterize § crystal morphology § particle size 27  Microscopy Crystal morphology: o Crystals are characterized by repetition of atoms or molecules in a regular 3-D structure. o There are six crystal systems (cubic, tetragonal, orthorhombic, monoclinic, triclinic and hexagonal) which have different internal structures and spatial arrangements. Particle size analysis: o particle size distribution of a sample can be important both for processability (powder flow, mixing, etc.) and for drug product performance (inhalers). § e.g. dissolution rate is directly proportional to surface area (inversely proportional to particle size). Find out: o other methods for determining particle size. 28  Assignment Read your lecture notes on: o Powder flow o Compression properties Find out the appropriate storage conditions for: o Tablets o Syrups o Reconstituted suspensions o Suppositories o Creams and lotions o Ophthalmic solutions o Reconstituted injections o Injections o Aerosols 29  Further Reading Gibson, M. (2009). Pharmaceutical preformulation and formulation: A practical guide from candidate drug selection to commercial dosage form. New York: Informa Healthcare. Aulton, M. E. (2002). Pharmaceutics: The science of dosage form design. Edinburgh: Churchill Livingstone. Sinko, P. J., & Martin, A. N. (2006). Martin's physical pharmacy and pharmaceutical sciences: Physical chemical and biopharmaceutical principles in the pharmaceutical sciences. Philadelphia: Lippincott Williams & Wilkins. Brittain, H.G.. (2014). Thermodynamic vs. kinetic solubility: Knowing which is which. American Pharmaceutical Review. 17. 30 END OF LECTURE UNIVERSITY OF HEALTH AND ALLIED SCIENCES School of Pharmacy