Solutions preformulation

Liquid paraffins, particularly those of low viscosity, have been used and are said to be of value for colored tablets, and even the use of modified vegetables has been attempted. However, they appear, in general, to offer little advantage over solid lubricants, and their incorporation into the precompression mixture is more difficult, requiring solution in a volatile liquid that is then sprayed onto the unlubricated material. Due to handling and EPA requirements, these materials are often rejected in the preformulation stage. 

Lipinski et al. [12] and Pan et al. [463] compared several commonly used methods of solubility measurement in early discovery, where samples are often introduced as 10 mM DMSO solutions. Turbidity-based and UV plate scanner-based detections systems were found to be useful. The methods most often used in discovery and in preformulation will be briefly summarized below. 

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

Drugs may also have more than two pKa values, such as polyprotic or polybasic compounds (e.g., minocycline), and such drugs exhibit a complex pH solubility profile. It is essential to know per se pH of the drug solution during preformulation studies. The pH is measured or theoretically calculated if the pKa and drug concentration C are known. The pH of a weak acid or the salt of a weak base and a strong acid can be calculated using the equation... 

The pH rate profile is an important parameter that is studied in the solution state. In early preformulation studies, an approximate pH rate profile is generated, usually including the pH encountered in salt selection and in vivo [55], The studies are later followed with a detailed pH profile in the whole pH range of 1-10. A typical pH rate profile is shown in Figure 18, which is useful to extract useful information on... 

An objective of preformulation scientist is to determine the equilibrium solubility of a drug substance under physiological pH to identify the BCS class of drug candidate for further development. For BCS classification the test conditions are strictly defined by the FDA. The pH solubility profile of the test drug substance should be determined at 37°C in aqueous media with a pH in the range of 1-7.5. Standard buffer solutions described in the USP are considered to be appropriate for use in these studies. A number of pH conditions are used bracketing the pKa value for the respective test substance. For example, for a drug with a Ka of 5, solubility should be determined at... 

By the time an active pharmaceutical ingredient (API) is made available to an analytical chemist in the formulation development group, most or all of the physical characteristics of an API has already been studied and the information should be available in some sort of a report from the drug substance group or preformulation group. Some of the key parameters that an analytical chemist in formulation development requires from such a report are the solubility and solution stability. 

Figure 9 Apparatus for preformulation testing of the kinetics of photostability of drugs in solution. Abbreviations V, reaction vessel ...

The tendency of a solid to take up water from the atmosphere, as it is subjected to a controlled RH program under isothermal conditions, is referred to as hygroscopicity (35). The hygroscopicity of a solid can be classified based on the amount or rate of water uptake when a solid is exposed to controlled RH values at a specified temperature (Table 1 from Ref. 35). The RH of a saturated solution of the API, RHo, can also be of importance. From a preformulation perspective, it is important to know the effect of water sorption on the pharmaceutically relevant properties of the API. 

The development of a nebulizer solution or suspension formulation is contingent on the same core preformulation data as would be required to support the development of any formulation. Physicochemical parameters such as pKa, log P,... 

Equally important in screening initial preformulations is the selection of a rubber stopper compatible with protein solutions. The variety of composition of mbber stoppers in parenteral formulations of biopharmaceuticals requires studies on compatibility with proteins, involving chemical extractants from the rubber composition into the protein solution over periods of stability at varying temperatures. We must also consider particle shedding from the stoppers into the protein solution, adsorption, absorption, permeation through the... 

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