Drug substances critical parameters

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]. 

Development studies, summarized within a distinct report on the physiochemical aspects, drug substance attributes, and finished product characteristics, become critical parts of the validation package. Such data is also valuable for future integration into a manufacturing operation. This includes the scientific rationale for formulating and bulk-handling procedures, lyophilization processing parameters, finished product analysis, and stability requirements. 

PQ is intended to demonstrate that the process will function correctly in its normal operating environment. The demonstration may involve pilot lots, commercial-scale lots, or carefully designed simulations of either. In the case of drug substances, PQ protocols often involve individual modules (e.g., steps, unit operations) of a new process prior to pilot or commercial scale-up of the full process. When a given critical process parameter cannot be simulated at less than commercial scale, all other process parameters are often established first, to avoid potential interference with the first commercial batch that must involve the sensitive parameter. The three full-size lots required to authorize commercial distribution can, if desired, represent key PQ experiments however, there is no limit to the number of subsequent commercial lots that can also continue to be considered part of the PQ step in a validation life cycle. 

Water solubility (or aqueous solubility) is the maximum amount of a given substance that can dissolve in pure water at a particular temperature. Water solubility is a critical parameter, as drugs hitting the stomach must dissolve (be soluble) in gastric fluids to enable their absorption, transport, and delivery to target organs (e.g. the liver). The solubility of a substance in water is also helpful in determining the dispersion and fate of chemicals in the environment, and for this, water solubility is related to other chemical parameters (e.g. the octanol-water partition coefficient KOW). 

Another critical parameter in the acid/base hydrolysis experiment involves incorporation of the appropriate controls. The critical controls are as is drug substance and acid only and base only at an appropriate concentration without the drug substance. Additionally, if elevated temperature is required, a thermal control sample should be run at the reaction temperature without acid... 

The particle size of a new drug substance is a critical parameter, as it affects every phase of formulation and its effectiveness. Appropriate particle size is required to achieve optimal dissolution rate in solid dosage forms, and to control sedimentation and flocculation in suspensions. Small particle size (2-5 gm) is required... 

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