Why is pharmaceutical preformulation important

Objective of preformulation study is to develop the elegant, stable, effective and safe dosage form by establishing kinetic rate profile, compatibility with the other ingredients and establish Physico-chemical parameter of new drug substances. Among these properties, drug solubility, partition coefficient, dissolution rate, polymorphic forms and stability are plays important role in preformulation study.

Currently, medications used in children are typically modified from pharmaceutical dosage forms designed for adults. Captopril is widely adapted to liquid formulations for use in hospitals. Its stability in the aqueous medium is reduced since it undergoes oxidation producing captopril disulfide its main metabolite. The aim of this formulation study was to suggest favorable conditions for the development of a stable captopril formulation.

The compatibility between the drug and excipients was evaluated by differential scanning calorimetry analysis DSC. For studies in solution, different formulations were prepared according to a factorial design varying EDTA concentration, water purity and pH.

The DSC curves obtained suggested, although not conclusive to elucidation, interactions of captopril with citric acid and sucralose. The stability study of these solutions revealed that the variables significantly influenced captopril content, which degraded at zero order kinetics and rates differing by a factor of up to 7 times, where pH proved the most influential factor.

Interactions between variables were observed. Therefore, development of a stable captopril formulation is feasible provided EDTA and a buffering agent is used at suitable concentrations 0. The available medications are mostly developed for adults. Thus, the data on safe dose is often extrapolated for pediatric use.

Children are subjected to therapy risk because they have different pharmacokinetic and pharmacodynamic mechanisms according to age and compared to adults Rosa et al. Medicamentos e pediatria. The need for modeling and simulation to design clinical investigations in children. J Clin Pharmacol. Dosing information in a standard drug reference: are pediatrics still therapeutically neglected? Pediatr Int. Thus, non-specific medicines for children can be classified as off-label, used with a different age, dose, frequency, presentation, other delivery route or indication to label guidelines Carvalho et al.

J Pediatr. Better medicines for children - where are we now, and where do we want to be? Br J Clin Pharmacol. Braz J Pharm Sci. Rio de Janeiro: Guanabara Koogan; Rev Latino-Am Enfermagem. Pediatric formulations: getting to the heart of the problem. Int J Pharm. Frequency of drug consumption and lack of pediatric formulations. Acta Pediatr Mex. Off-label and unlicensed drug utilization in hospitalized children in Fortaleza, Brazil.

Eur J Clin Pharmacol. Lack of drug preparations for use in children in Brazil. The problem of childhood hypertension has only received greater attention, so few medications have been developed and tested on children. Hypertension in the young: epidemiology, sequelae and therapy. Nephrol Dial Transplant. The development of a liquid formulation of captopril for pediatric use is challenging owing to its susceptibility to oxidative degradation facilitated by high humidity and catalyzed by metal traces commonly found in excipients Marcatto et al.

Moreover, these preparations must provide safe excipients and good palatability, as the medications mostly have a bitter, sour or salty taste Hempenstall, Tuleu, Hempenstall J, Tuleu C.

Areas covered: This article describes the significance of preformulation research in drug discovery and development. Various crucial preformulation parameters with case studies have been discussed. For example, during synthesis of ethinylestradiol, crystallization of final product is achieved by using solvents like acetonitrile, chloroform, methanol, and water.

As a result, four different solvates are generated. Differentiation of pseudopolymorphs can be studied by hot stage microscopy melting behavior. True polymorphs melt slightly and form a globule, while pseudopolymorphs give bubble in the system due to generation of vapor or gas from entrapped solvent. With respect to stability and solubility, again polymorphs can be classified as stable and metastable polymorphs.

Stable polymorph is one of the most physically stable polymorphic forms and has highest melting point, lowest energy, and least aqueous solubility, while metastable polymorph refers to forms other than stable polymorph and has highest energy, low melting point, highest aqueous solubility, and hence shows better bioavailability. Metastable polymorphs have wider application in developing formulation but still only one-tenth of metastable forms are having practical use as they suffer from the stability issues [ 13 ].

Hygroscopicity can be defined as the capacity of a compound to absorb atmospheric moisture. Amount of moisture absorbed depends on atmospheric conditions and surface area. Deliquescent substance absorbs moisture to a greater extent and liquefies itself.

The main reason behind study of this property is because changes in the moisture level can influence chemical stability, flowability, and compressibility to a greater extent. Slightly hygroscopic: After abovementioned storage condition, if overall increase in weight is greater or equal to 0. Hygroscopic: After abovementioned storage condition, if overall increase in weight is greater or equal to 0.

For this study, samples under analysis are exposed to range of controlled relative humidity prepared with saturated aqueous salt solutions Table 4. One can link flowability and relative humidity by amount of moisture uptake Table 5. Moisture level uptake can be monitored by techniques like thermogravimetric analysis TGA , Karl Fischer titration, and gas chromatography.

Particle size greatly affects a number of quality parameters like dissolution rate, solubility, bioavailability, content uniformity, and lack of grittiness. Application of particle size study during preformulation stage is described as follows: When solubility is major issue, one may significantly improve the solubility by reducing the particle size increased surface area.

In case of suspension, particle size is the most important parameter, which determines the stability and quality of formulation. Too much reduction in the particle size leads to generation of charged particle and hence unstable system. On other hand, larger particle size leads to caking. Due to nonuniform particle size distribution, there is significant risk associated with content uniformity in case of potent formulations.

A number of methods are available to determine particle size, which are as follows: Microscopy. Apart from particle size, particle shape plays an important role during preformulation phase as the shape of particle may influence surface area, flow properties, and compaction force.

A drug particle may exist in different forms like spherical, angular, acicular, needle, oval, or rough. It is a well-accepted fact that a spherical particle has the maximum area and uniform flow property. The maximum surface area ensures the better solubility. For topical products that are working as abrasives, irregular particle shape is more preferred. Table 3 provides idea about various methods, which can control particle shape and size and provide better results needed to design a formulation.

Density can be defined as ratio of mass of a substance to its volume, which greatly depends on particle size distribution and shape. The main problem arises during determination of bulk volume is the voids, which can be interparticulate, open, and closed intraparticulate.

So by considering the presence of different types of void volume, various densities are proposed. True density: It is defined as total volume of solids excluding all space greater than molecule diameter. True density can be measured with helium pycnometer.

Bulk density: It is defined as total volume occupied by entire powder mass. It can be determined by placing previously sieved powder bulk into a graduated cylinder and measuring the volume in milliliters. Division of original weight and attended volume gives idea about bulk density.

Tapped density: It is determined by placing graduated cylinder containing known weight of sample on tapped density apparatus and is operated for the fixed number of taps until a constant volume is attained.

Ratio of total amount of substance taken to the final constant volume gives idea about tapped density. One needs to gain knowledge about the size and type of dosage form and is the most critical parameter for the low potency drugs. In most of the cases, two types of density are studied, namely, bulk density and tapped density. Following problems can be addressed related to density: With drugs having low density, the bulk becomes more and hence capsule formulation is quite difficult to formulate as capsule can incorporate limited volume.

In development of tablet formulation, low-density drug creates difficulties as they are having low compressibility and hardness in tablet is difficult to achieve. If the difference of density is more between drug substances and excipientis more, homogeneity in the formulation is difficult to achieve. Flow property of material can be affected by a number of factors including frictional forces, surface tension forces, electric forces, and van der Waals forces.

Efficient flow of drug substance powder is needed for effective tablet formulation. The main reason behind inclusion of this parameter in preformulation is its linkage with other physical parameters like hygroscopicity and particle size and shape. Importance of flow property is even more when dose loading is more. Table 6 gives outline on correlation of flow properties of a material with moisture uptake at different humidity levels.

In case of hygroscopic material, flow property of drug tends to deteriorate as the presence of absorbed moisture increases cohesiveness. Irregular particle size and nonuniform shape can also disturb normal flow property of drug.

Another way of measuring flow property is angle of repose, which provides the idea resistance to the movement of particle. It can be represented by the following formula:. It is the maximum angle that can be obtained between height of pile and a horizontal plane. It gives a brief idea about internal cohesive and frictional levels. There are basically two types of methods that are available, which are as follows:. Static angle of repose Fixed funnel method.

Dynamic angle of repose Rotating cylinder method. Excipients are added along with the active pharmaceutical ingredient in formulations. Most excipients possess biological activity but having role in administration, mediating the release of the active component, and providing stability against degradation.

So study about interaction between active ingredient and inactive ingredient can provide idea about type of incompatibility and the justification behind the inactive ingredient selection [ 14 ]. Change in organoleptic properties of formulation. In general, one can say that drug-excipient incompatibility may result in change in physical, chemical, microbiological, or therapeutic properties of formulation. In such an instance, active pharmaceutical ingredient and excipients interact without undergoing changes involving like breaking or formation of new bonds.

The resulting drug product retains its original chemical properties but may involve changes such as alteration in physical properties. Such interaction results in changes like change in color, odor, flow properties, and sedimentation rate. Such an example of physical incompatibility is between tetracycline and calcium carbonate. It results in formation of insoluble complex with calcium carbonate, leading to slower dissolution and decreased absorption in the gastrointestinal tract [ 15 ].

In such incompatibility, there is interaction of active pharmaceutical ingredient and excipient through chemical degradation pathway. The chemical reaction involves bond breakage or new bond formation to produce an unstable chemical entity.

Chemical reaction may take place as hydrolysis, oxidation racemization, and Maillard reactions. The resulting changes are more deleterious than physical incompatibility. This type of incompatibility can be assessed by chromatographic studies.

Such interaction is also referred to as biopharmaceutical interaction, but it differs from previously discussed incompatibilities in a way that interaction will take place once the formulation is administered into the body. Such type of incompatibility is associated with alteration in drug absorption in the body.