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Abstract. The physical-chemical properties of interest for Controlled Release (CR) dosage form development presented are based on the author's experience. Part I addresses selection of the final form based on a logical progression of physical-chemical properties evaluation of candidate forms and elimination of forms with undesirable properties from further evaluation in order to simplify final form selection. Several candidate forms which could include salt, free base or acid, polymorphic and amorphic forms of a new chemical entity (NCE) or existing drug substance (DS) are prepared and evaluated for critical properties in a scheme relevant to manufacturing processes, predictive of problems, requiring small amounts of test materials and simple analytical tools. A stability indicating assay is not needed to initiate the evaluation. This process is applicable to CR and immediate release (IR) dosage form development. The critical properties evaluated are melting, crystallinity, solubilities in water, 0.1 N HCl, and SIF, hygrodymamics, i.e., moisture sorption and loss at extremes of RH, and LOD at typical wet granulation drying conditions, and processability, i.e., corrosivity, and filming and/or sticking upon compression.

INTRODUCTION

These papers present an overview of the physical- chemical properties relevant to the development of Controlled Release (CR) dosage forms. The overview is presented as a preformulation scheme using practical examples representing the experience of the author. Part I-Candidate Selection, describes the initial preformulation support phase in which candidate forms or a solo form are evaluated, from which optimal forms are identified, and a final form for continued development is selected. The selection process follows a logical path in which forms with undesirable properties are eliminated from further study reducing the number of candidates and simplifying selection of a final form for dosage form development.

Preformulation support is neither new nor novel to dosage form development. It is more frequently applied to immediate release (IR) dosage form development than to CR dosage form development, because most new chemical entities (NCEs) are developed as IR dosage forms, and CR is usually used in line extension to extend the life cycle of an existing drug substance (DS). However, CR dosage form development is applicable at any stage of development.

The term form applies to a specific NCE or DS salt, free base or free acid, polymorph or amorph. During the discovery phase, an NCE is usually synthesized in very small batch sizes, e.g., =5 g, and recovered by recrystallization as a salt form that is easily isolated, dependent upon experience and preference. In many pharmaceutical firms, the promotion of an NCE from discovery to development status results in the preparation of additional candidate forms that are evaluated for their physical-chemical properties in order to identify optimal forms from which a final form is selected for dosage form, preclinical, clinical and commercial development. This same tactic can be applied to any DS intended for line extension as a CR dosage form.

The very first scale up batch of an NCE is usually small in size, likely to be 25 to 50 g in size, and is intended to be shared for use in preformulation support and preclinical dose ranging studies. The number of forms that can be made is limited by the availability of the NCE and number of forms that are successfully prepared. Some laboratories engage in deliberate attempts to create new polymorphs. These experiments might be better suited for the next phase of development after selection of a final form and more DS is available. Also, accidental creation and discovery of polymorphic forms is more likely during the next phase of development. For these reasons polymorphism is discussed in Part II.

The primary objectives of preformulation support for CR and IR dosage forms are the same, to select an optimal form of an NCE or DS for development and provide adequate physical-chemical characterization of the candidate to facilitate dosage form development. In instances where chemistry, patents, or contracts limit the form to one form, that one form is evaluated to identify its physical-chemical properties and to identify its strengths and weaknesses.

The physical-chemical characterization of the forms should be quick and involve evaluations that are relevant to the expected dosage form manufacture, predictive of potential processing problems, require small amounts (5 to 7 g) of NCE or DS and easily available analytical tools, and not require a stability indicating assay.

The methods presented were derived and used to resolve problems that occurred previously. Simple analytical tools are used for much of the evaluation. X-ray powder diffraction (XRD) and DSC analysis are available from contract laboratories if not available in house. Chromatographic analysis is preferred for solubility measurements.

PROPOSED PREFORMULATION SCHEME

The applicability of the proposed preformulation scheme can be demonstrated with a review of the needs for CR dosage form development. CR can be created by reducing the rate of dissolution by increasing the particle size, creating matrices with waxes and polymers using heat or physical mixtures, applying cellulosic or pH sensitive polymers to tablets, particles or beads, formation of salts with ion exchange resins or salts such as pamoate and tannates which are practically insoluble in aqueous media. Controlled dissolution of more soluble salt forms can be created to deliver NCEs/DSs over 8, 12 and 24- h periods using osmotic pumps and pore forming systems. Pulsatile delivery systems that use pH sensitive polymers to release a DS at specific sites within the GI tract have created once daily dosing regimens for products that previously required two to three times a day dosing. Effective once a day dosing has also been achieved for a DS with an inherently long half-life originally formulated as an IR low dose two to four times a day dosage form by increasing the strength of the tablets 5- to 20-fold. GI residence times and absorption capabilities have been used to create CR by employing mucoadhesives and geometric forms to increase stomach residence times. And an apparently reverse CR tablet product is marketed in which a CR coat limits dissolution in the upper GI, and an IR core quickly releases the DS into the lower GI where there is limited absorption through the GI lumen.

The physical-chemical and pharmaceutical properties that are candidate form dependent and critical to the selection process are: melting behavior and crystallinity; processability, i.e., measuring the potential for filming and sticking on compression, and corrosivity (tablet press turret) at ambient room temperature and 83%RH; critical solubilities at ambient room temperature in water, hydrochloric acid, 0.1 N, and Simulated Intestinal Fluid, pH 6.8 (current) or 7.4 (previous USPs); hygrodynamics, weight change after drying at 49° or 50°C for 16 to 24 h; and storage for 1 week at ambient temperature and extremes of humidity, 11% RH and 83% RH, respectively. These properties are of interest to both CR and IR dosage form development.

CANDIDATE SELECTION

The 1977 publication, Pharmaceutical salts by Berge, Bighley and Monkhouse (1) is the primary source for identifying potential candidate salt forms for evaluation and selection of a form for development. It lists over 100 organic and inorganic anionic and cationic salts of drug substances (DSs) in marketed products at the time of publication. Several strategies might be employed based on the criteria for creating CR. One strategy could be to prepare salt forms that are poorly soluble or practically insoluble in water in the range pH 1.3 to 6.8 or 7.4. Another strategy would be to prepare a number of salts that include aliphatic, aromatic, sulfonic acid and inorganic salts and determine which have properties most applicable to the intended mechanism or delivery system. The number of salts prepared is dependent upon the availability of the NCE/DS and the success of salt formation trials. In exceptional cases more forms may be prepared until a form with optimal or nearly optimal properties is identified.

The term optimal form is used because of the impracticality of determining the best form. Optimal forms are the forms that comply best with the intended mechanism or delivery system and meet applicable patents and purity requirements for the NCE/DS. In some cases the NCE or DS form may be dictated by patent, contract or chemistry and there is only one form for evaluation. And in some cases, the optimal form may have one or more undesirable properties. A complete description of the analytical methods has been omitted; however, they are available upon request.

PRACTICAL EXAMPLE OF CANDIDATE FORM SELECTION

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Frank A. Chrzanowski, Ph.D. is a Pharmaceutical Consultant, Pharmaceutical Development Scientist, and Expert Witness having more than 30 years experience in the field. He has been an Expert Witness for US and Canadian Pharma Companies and Law Firms in Pharmaceutical Formulation Patent Litigation, including Hatch-Waxman Innovator vs. Generic Products, In-Licensing Due Diligence, and Civil Suits involving Commissions and Technology.

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