Chapter 1 Preformulation.pdf

Industrial Pharmacy Dr Nisrein Jaber 2023-2024 1st Semester Industrial Pharmacy Chapter I Pharmaceutical Preformulation Introduction Departments of a pharmaceutical firm 1. Research and development (R&D) • Pre-formulation, optimization, scale up, analytical method development, setting up spec...

Industrial Pharmacy Dr Nisrein Jaber 2023-2024 1st Semester Industrial Pharmacy Chapter I Pharmaceutical Preformulation Introduction Departments of a pharmaceutical firm 1. Research and development (R&D) • Pre-formulation, optimization, scale up, analytical method development, setting up specifications for raw materials, process validation • Small scale laboratory, pilot scale up. Departments of a pharmaceutical firm 2. Production department • Large scale manufacturing according to the formulation and procedure developed by R&D • Milling, mixing, granulation, tableting on a large scale process validation. Departments of a pharmaceutical firm 3. QC department • Sampling and testing semi-finished and finished products • Analytical labs (UV, HPLC) follow test procedures developed by R&D • Process validation Departments of a pharmaceutical firm 4. QA department • Makes sure that GMPs are being applied by overseeing the practices followed during manufacturing • Process validation 7 The Industrial Pharmacy  Is to focus on process technology and dosage form design.  The pharmaceutical industry looking for robust formulations and process technologies, which should enable to shorten the development time and to increase the product quality. 8 • A close cooperation with the pharmaceutical industry is a prerequisite to be able to do studies in the area of scale-up and understand and control pharmaceutical processes, such as tableting, capsule filling, moist agglomeration, atmospheric spray drying , freezedrying, and protein degradation during filling and dosing. • Furthermore our aims are to design and develop new devices to improve the pharmaceutical processes and avoid scale-up problems. 9 The concept of preformulation Formulation is the process of developing a drug candidate into a drug product. Objective : The main objective is to generate information useful to the formulation in developing most stable and bioavailable dosage form that mass can be produced. 10 Preformulation influences a) selection of the drug candidate itself b) selection of formulation components c) API and drug product manufacturing processes d) determination of the most appropriate container closure system e) development of analytical methods f ) assignment of API retest periods g) the synthetic route of API 11 • The decision to select a successful drug candidate to be developed does not depend on pharmacological efficacy alone. In practice, the physicochemical properties of the molecule affect how a material will be processed pharmaceutically, its stability, its interaction with excipients and how it will transfer to solution and, ultimately, will determine its bioavailability. 12 It follows that characterizing the physicochemical properties of drug candidates early in the development process will provide the fundamental knowledge base upon which candidate selection, and ultimately dosage form design, can be made, reducing development time and costs. Physicochemical properties can be split into those that are intrinsic to the molecule and those that are derived from bulk behaviour (e.g. of the powder or crystals). 13  Intrinsic properties are inherent to the molecule and so can only be altered by chemical modification, whereas derived properties are the result of intermolecular interactions and so can be affected by the solid-state form, physical shape and environment among other factors. Determination of these properties for a new chemical entity is termed preformulation (i-e the stage that must be undertaken before formulation proper can begin). 14 Development of a suitable assay is the first step of preformulation. Note that at this stage the determination of approximate values is acceptable so as to make a ‘go/ no go’ decision in respect of a particular drug candidate, and so assays do not need to be as rigorously validated as they do later in formulation development. 15 Drug Physicochemical Properties 16 1- Organoleptic properties 17  Color:  Color can be useful when describing different batches of drug it can sometimes be used as an indicator of solvent presence or, more importantly, of degradation. In addition, subtle differences in colour may be due to variations in the particle size distribution.  Usually colour is subjective and is based on individual perception; however, more quantitative measurements can be obtained by using, e.g colorimetry 18  Color is generally a function of a drug’s inherent chemical structure relating to a certain level of unsaturation.  Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores.  Some compounds may appear to have color although structurally saturated. 19 Odor:  No strong odors should be present.  Any deviation from the substance’s characteristic odour is to be considered and checked for degradations in the substance 20 Taste Unpalatability could be suppressed by: coating flavors excipients But this could leads to problems in solubility, Particle Size ,..etc 21 22  Once these properties are known, further macroscopic (or bulk) properties of the drug candidate can be measured  These properties result from intermolecular interactions.  Note also that determination of the chemical structure is not required, as it is assumed the chemists preparing the candidate molecules will provide this information.  Note also that solubility will be dependent on the physical form (polymorph, pseudopolymorph or amorphous). 23 24 2- Solubility  It is the first physicochemical parameter to be determined.  The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature.  In the other words the solubility can also be defined as the ability of one substance to form a solution with another substance. The substance to be dissolved is called as solute and the dissolving fluid in which the solute dissolve is called as solvent, which together form a solution. The process of dissolving solute into solvent is called as solution, or hydration if the solvent is water 25  No drug will enter systemic circulation and reach its ultimate therapeutic target without first being in solution.  Relatively insoluble compounds often exhibit incomplete or erratic absorption.  Up to 40% of drug candidates have been abandoned because of poor aqueous solubility.  Early determination of solubility gives a good indicator as to the ease of formulation of a drug candidate. 26 Initial formulations, used for obtaining toxicity and bioavailability data in animal models, will need to be liquids for oral gavage or intravenous delivery, and a solubility greater than 1 mg mL−1 is usually acceptable.  For the final product, assuming oral delivery in a solid form, solubility of the molecule greater than 10 mg mL−1 is preferable. 27 28 • A drug’s solubility is usually determined by the equilibrium solubility method, by which an excess of the drug is placed in a solvent and shaken at a constant temperature over a long period until equilibrium is obtained. Chemical analysis of the drug content in solution is performed to determine degree of solubility. 29 • The methods to increase drug solubility depend on the chemical nature of the drug and the type of drug product under consideration. Chemical modification of the drug into salt or ester forms is frequently used to increase solubility. • If the solubility of the drug candidate is less than 1 mg mL−1, then salt formation, if possible, is indicated. Where solubility cannot be manipulated through salt formation, then a novel dosage form will be required. 30 • Many drugs are ionizable organic compounds, and thus there are a number of parameters that will determine the solubility of a compound. These parameters include, e.g., molecular size and substituent groups on the molecule, degree of ionization, ionic strength, salt form, temperature, crystal properties and complexation. • The solubility of every new drug must be determined as a function of pH over the physiological pH 31 32 Pharmaceutical Applications of Solubility • To obtain a homogenous distribution of small • • • • amount of drugs at solid state. To stabilize unstable drugs. To dispense liquid or gaseous compounds. To formulate a faster release priming dose in a sustained release dosage form. To formulate sustained release dosage or prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers. 33 Applications of solubilization  Drugs with limited aqueous solubility can be solubilized. These include oil-soluble vitamins, steroid hormones and antimicrobial agents etc.  Solubilization of orally administered drugs results in an improved unpleasant taste. appearance and improves  Both oil-soluble and water-soluble compounds can be combined in a single phase system as in case of multivitamin preparations. 34 Solubilization may lead to enhanced absorption and increased biological activity.  Improves the intestinal absorption of vitamin A.  Drug absorption from ointment bases and suppositories also increased. 35 Aqueous concentrates of volatile oils can be prepared by solubilization.  Example: soaps used for solubilising phenolic compounds for use as disinfectantsLysol, Roxenol etc.  Barbiturates, anticoagulant, alkloidal drugs are dissolved with polysorbate by solubilization. High aqueous solubility does not necessarily mean that a compound will exhibit satisfactory absorption. 36 3- Molecular dissociation  Determining the pKa of a drug is the next step in preformulation characterization.  Approximately two-thirds of marketed drugs ionize between pH 2 and pH 12  Understanding acid and base behaviour is thus extremely important, not only because of the number of ionizable drugs available, but also because the solubility of an acidic or basic drug will be pH dependent (and because possession of an ionizable group opens up the possibility of solubility manipulation via salt formation). 37 This is particularly important with drugs intended for peroral administration as they will experience a range of pH environments, and it is important to know how their degree of ionization may change during passage along the gastrointestinal tract. 38 The Henderson–Hasselbalch equations allow calculation of the extent of ionization of a drug as a function of pH, if the pKa is known. When the pH is significantly below the pKa (by at least 2 pH units), a weakly acidic drug will be completely un-ionized, and when the pH is significantly above the pKa (by at least 2 pH units), a weakly acidic drug will be virtually fully ionized (and vice versa for a basic drug) 39 The degree of ionization will affect solubility because ionized species are more freely soluble in water. Measurement of pKa: • Modern automated instrumentation is available that can determine pKa values with very small amounts of drug (typically 10 mg to 20 mg). • This is extremely useful in the context of preformulation, where material is scarce. 40 • Usually this instrumentation is based on a potentiometric pH titration. The drug is dissolved in water, forming either a weakly acidic or a weakly basic solution. Acid or base (as appropriate) is titrated and the solution pH recorded. A plot of volume of titrant solution added versus pH allows graphical determination of the pKa, because when pH = pKa, the compound is 50% ionized. This method has the significant advantage of not requiring an assay. 41 4- Partitioning • No solute has complete affinity for either a hydrophilic or a lipophilic phase. In the context of preformulation, it is important to know early in the development stage how a molecule (or charged ion) will distribute itself between aqueous and fatty environments (e.g. between gut contents and lipid biological bilayers in the surrounding cell walls). 42 • In a physiological environment, drugs partitions from an aqueous phase to numerous and complex lipophilic phases (typically various cell membranes). • It would be difficult to develop an analytical method that allowed measurement of actual partitioning between such complex phases, and so a simple solvent model, commonly using n-octanol, is usually used instead. nOctanol is taken to mimic the short-chain hydrocarbons that make up many biological lipid bilayers. 43 • A partition coefficient for the partitioning of a solute between water (w) and n-octanol (o) can be written as: 44 45 • Log P values can be determined experimentally or can be calculated from the chemical structure of the drug candidate by means of group additivity functions. 46 5- Hygroscopicity • Hygroscopicity refers to the tendency of a substance to attract water from its immediate environment, either by absorption or by adsorption. • An increase in water content usually results in a change in physicochemical properties. • Typically, wet powders will become more cohesive and flowability is reduced. • Water also acts to mediate many solid-state reactions, so an increase in water content can often increase the rate of chemical degradation of the active ingredient or interaction with any excipients. 47 • If the substance is amorphous, then absorption of water causes plasticization of the matrix (effectively the molecular mobility of the molecules is increased) and then major structural change. • If the amorphous matrix is a freeze-dried powder, then absorption of water often causes structural collapse. • At the extreme, absorption of water will cause amorphous materials to crystallize. 48 Hygroscopicity affects compression characteristic , granulation & hardness of final tablet. It also affects compaction. Important in aerosol. Affects chemical stability of hydrolysable drug. 49 • Salts, in particular, usually have a greater propensity to absorb water than the corresponding free acid or base, so the stability of salt forms with respect to environmental humidity must be assured. Some salts (e.g., potassium hydroxide or magnesium chloride) are so hygroscopic they will dissolve in the water they absorb, forming solutions. 50 • If water absorption is likely to cause a detrimental change in physicochemical properties, the appropriate steps must be taken to protect the drug candidate or drug product. Typically, this would involve selection of suitable packaging and advising the patient on correct storage. 51  List of examples: Hygroscopic & Deliquescent Efflorescent Ephedrine atropine Hyoscymine cocaine Phenobarbital codeine Pilocarpine scopolamine Physostigmine caffeine Glycerinated gelatin & PEG base of suppository are hygroscopic in nature 52 • Water uptake is usually determined through a change in mass (although chemical approaches, such as Karl Fischer titration, can also be used). • TGA measures mass as a function of temperature, whilst DVS measures mass as a function of humidity at a constant temperature. 53 6-Physical form • The solid state is probably the most important state when one is considering development of a drug candidate into a drug product. • Many solid-state (or physical) forms may be available, and each will have different physicochemical properties (including solubility, dissolution rate, surface energy, crystal habit, strength, flowability and compressibility). 54 Polymorphism: • When a compound can crystallize to more than one unit cell (i.e. the molecules in the unit cells are arranged in different patterns), it is said to be polymorphic • The form with the highest melting temperature (and by definition the lowest volume) is called the stable polymorphic form, and all other forms are metastable. • Different polymorphs have different physicochemical properties, so it is important to select the best form for development. 55 • A defining characteristic of the stable form is that it is the only form that can be considered to be at a thermodynamic position of equilibrium (which means that over time all metastable forms will eventually convert to the stable form). It is tempting therefore to consider formulating only the stable polymorph of a drug, as this ensures there can be no change in polymorph on storage. 56 • The stable form might, however, have the worst processability (e.g., the stable form I of paracetamol has poor compressibility, whilst the metastable form II has good compressibility), or lowest bioavailability (e.g., the presence of the B form or the C form of chloramphenicol palmitate dramatically reduces bioavailability). • Selection of polymorphic form is not necessarily straightforward, although if the stable polymorph shows acceptable bioavailability, then it is of course the best option for development. 57 • XRPD provides structural data to identify and differentiate polymorphs 58 • DSC data differentiate polymorphs on the basis of their melting points and heats of fusion, thus providing thermodynamic information. This means DSC can identify which polymorph is stable and which polymorphs are metastable. In addition, the heat of fusion can be used to calculate ideal solubility. 59 • Amorphous materials: • Several factors can make it difficult for molecules to orient themselves, in large numbers, into repeating arrays. • One is if the molecular weight of the compound is very high (e.g. if the active ingredient is a derivatized polymer or a biological material). • Another factor is if the solid phase is formed very rapidly (say, by quench-cooling or precipitation), wherein the molecules do not have sufficient time to align. 60 • It is also possible to disrupt a preexisting crystal structure with application of a localized force (e.g. by milling). In any of these cases the solid phase so produced cannot be characterized by a repeating unit cell arrangement, and the matrix is termed amorphous • Because amorphous materials have no lattice energy and are essentially unstable (over time they will convert to a crystalline form), they usually have appreciably higher solubilities and faster dissolution rates than their crystalline equivalents, and so offer an alternative to salt selection as a strategy to increase the bioavailability of poorly soluble compounds. 61 Powder properties • Manufacturing processes frequently involve the movement, blending, manipulation and compression of powders and so will be affected by powder properties. 62 1- Particle size and shape • Particle shape is most easily determined by visual inspection with a microscope. • Usually a light microscope will suffice, unless the material is a spray-dried or micronized powder, in which case scanning electron microscopy might be a better option. • If the particles are not spherical but are irregularly shaped, it is difficult to define exactly which dimension should be used to define the particle size. 63 64 • Bulk flow, formulation homogeneity, and surface-area controlled processes such as dissolution and Surface morphology of the drug particles. • In general, each new drug candidate should be tested during preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug’ s surface area for interactions. 65 Surface area Particle size & surface area are inversely related to each other: smaller the drug particle, greater the surface area. 66 • Relatively high surface area most often reflects a relatively small particle size, except porous or strongly agglomerated mass • Small particles (thus of high surface area) agglomerate more readily, and often to render the inner pores and surface accessible to dissolution. 67 • Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. 68 • It is generally recognized that poorly soluble drugs showing a dissolution- rate limiting step in the absorption process and will be more readily bioavailable when administered in a finely subdivided state rather than as a coarse material. In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipients than are coarse materials 69 • Influences of Particle Size  Particle size influences dissolution  Particle size influences flow properties of powders  Particle size influences stability of dispersions  Particle size influences Texture and feel or lacking of grittiness.  Particle size influences bioavailability and therapeutic effectiveness  Particle size in inhaler formulation, ophthalmic formulation. 70 71 2- Powder flow • Powders must have good flow properties to fill tablet presses or capsule-filling machines and to ensure blend uniformity when mixed with excipients. • Assessment of powder flow is easy when large volumes of material are available, but during preformulation, methods must be used that require only small volumes of powder. The two most relevant methods of assessment at the preformulation stage involve the measurement of the angle of repose and measurement of bulk density. 72 • The angle of repose, Carr’s index and the Hausner ratio (the latter two are both calculated from measurements of bulk density) have proved to be the most useful parameters in predicting bulk properties when only a small amount of test material is available 73 Compaction properties • Compaction is a result of the compression and cohesion properties of a drug . • These properties are usually very poor for most drug powders, but tablets are rarely made from the drug alone. 74 • Excipients with good compaction properties are added. With low-dose drugs, the majority of the tablet comprises excipients and so the properties of the drug are less important. However, once the dose increases to more than 50 mg, the compaction characteristics of the drug will greatly influence the overall properties of the tablet. 75 • Information on the compaction properties of a drug candidate is very useful at the preformulation stage. • A material to be tableted should preferably have plastic properties (i.e. once deformed it should remain deformed), but brittleness is also a beneficial characteristic, because the creation of fresh surfaces during fragmentation facilitates bond formation. 76 • Water content may also be important as water frequently acts as a plasticizer, altering mechanical properties. • A useful practical guide is that if a high-dose drug behaves plastically, the excipients should fragment. • Otherwise the excipients should deform plastically. 77 The End 78