Drug substance parameters

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Since full analyses are carried out, a lot of data are generated. Every parameter is reviewed for trends that signal product aging or outright decomposition of the active principle this can be as cosmetic in nature as discoloration or as potentially hazardous as buildup of toxic derivatives. If the drug substance is an ester, for example, hydrolysis, particularly if moisture penetrates the primary packaging material, will decompose the compound into its acid and alcohol components. From a pharmaceutical or medical viewpoint, even if there is no toxicity issue involved, this will result in a loss of bioavailability. Even this is to be avoided because subpotency introduces therapeutic uncertainty and can go as far as lethal undertreatment. 

The goals of the program are, therefore, (1) to establish the necessary physicochemical parameters of a new drug substance, (2) to determine its kinetic rate profile,... 

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]. 

XRPD as a stability-indicating assay method When the phase identity, or degree of crystallinity (or lack thereof), of a drug substance is important to its performance in a drug product, XRPD can serve as a vital stability-indicating assay method. There is no doubt that XRPD can be validated to the status of any other stability-indicating assay, and that one can use the usual criteria of method validation to establish the performance parameters of the method. This aspect would... 

What are the various physical parameters that ultimately establish the purity of a drug substance Explain with appropriate examples. 

Prior to formulating a drug substance into a dosage form, the desired product type must be detemined for planning the product formulation activities. Then, various initial formulations are developed and then evaluated for selected parameters, such as drug-release profile, bioavailability, clinical effectiveness, and for any scale-up problems. The best formulation is selected and becomes the master formula. Each batch of the product subsequently prepared must meet the specifications established in this master formula. 

Eollowing finalization of drug substance synthetic routes and drug product formulation, the focus shifts to the development of robust and transferable methods for post-approval support at quality control units. It is important to remember during the final stage of method development that achievement of separation conditions is only one of the necessary parameters for successful method implementation. Extensive studies to measure robustness and quantitative method performance are conducted to assure that the method performs as intended in quality control laboratories. It should be emphasized that successful method development requires extensive cooperation between the development laboratory and the receiving quality control laboratories. 

TABLE 2 System Suitability Test Parameters Typically Applied in Testing of Drug Substance and Drug Product Materials... 

The use of compaction simulators was first reported in 1976. Since then, a variety of simulators have been developed. Hydraulic simulators, as well as mechanical simulators, are available to characterize raw materials, drug substances, and formulations, as well as to predict material behavior on scale-up. The appeal of simulators is due to the fact that they purport to provide the same compaction profile as experienced on a tablet press while using only gram or even milligram quantities of powders. Compaction simulators can achieve high speeds, as would be experienced on a production tablet press, and can be instrumented to measure a variety of parameters, including upper and lower punch force, upper and lower punch displacement, ejection force, radial die wall force, take-off force, etc. Summaries on the uses of simulators and tablet press instrumentation can be found in (19,20). 

The Tandem system (Bruker Optics) is available for use during tablet production to measure tablet weight, thickness, hardness, and diameter, as well as online NIR content uniformity. The system can provide online analysis for drug substance uniformity, moisture content, and excipients. The advantage of systems like this is that the necessary data are available immediately to make adjustments to the production parameters in order to improve product rmiformity. Therefore, adjustments can be made to tablet weight in real time in order to achieve 100% of the label claim. 

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