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Abstract. Practical examples of preformulation support of the form selected for formulation development are provided using several drug substances (DSs). The examples include determination of the solubilities vs. pH particularly for the range pH 1 to 8 because of its relationship to gastrointestinal (GI) conditions and dissolution method development. The advantages of equilibrium solubility and trial solubility methods are described. The equilibrium method is related to detecting polymorphism and the trial solubility method, to simplifying difficult solubility problems. An example of two polymorphs existing in mixtures of DS is presented in which one of the forms is very unstable. Accelerating stability studies are used in conjunction with HPLC and quantitative X-ray powder diffraction (QXRD) to demonstrate the differences in chemical and polymorphic stabilities. The results from two model excipient compatibility methods are compared to determine which has better predictive accuracy for room temperature stability. A DSC (calorimetric) method and an isothermal stress with quantitative analysis (ISQA) method that simulates wet granulation conditions were compared using a 2 year room temperature sample set as reference. An example of a pH stability profile for understanding stability and extrapolating stability to other environments is provided. The pH-stability of omeprazole and lansoprazole, which are extremely unstable in acidic and even mildly acidic conditions, are related to the formulation of delayed release dosage forms and the resolution of the problem associated with free carboxyl groups from the enteric coating polymers reacting with the DSs. Dissolution method requirements for CR dosage forms are discussed. The applicability of a modified disintegration time (DT) apparatus for supporting CR dosage form development of a pH sensitive DS at a specific pH such as duodenal pH 5.6 is related. This method is applicable for DSs such as peptides, proteins, enzymes and natural products where physical observation can be used in place of a difficult to perform analytical method, saving resources and providing rapid preformulation support.

INTRODUCTION

This section deals with preformulation support after selection of a final candidate form. This phase of pharmaceutical development begins with the scaling up of the synthesis and recrystallization of the selected DS form in order to provide adequate supplies for preclinical, dosage form, and clinical development. These activities increase the availability of DS for additional preformulation support as described in Table I. Controlled release CR dosage form development may require modification or remediation of DS properties.Preclinical, dosage form, dissolution method, and analytical method development are dependent upon the physical- chemical properties and characterizations described in Table I.

A complete review of all of the preformulation activities in Table I is impractical. However most of the important considerations supporting development are reviewed. The presentation of examples of preformulation support in this phase of development continues with determination of the pHsolubility profile of Mc-5707 free base (Fig. 1), demonstrating how the solubilities of McN-5707 are expanded beyond the original determinations during the previous phase of candidate form selection. Additional examples of preformulation support are provided using other DSs because they provide better opportunities to present a topic. Three novel methodologies for characterizing DS properties such as solubilities, drugexcipient compatibilities, and dosage form dissolution testing are also reviewed. A complete description of the methods used is also impractical. However, they are available upon request.

Preformulation Considerations

The properties of a DS form such as its solubilities vs. pH and solvents, pH-stability profile, compatibilities with excipients, polymorphic behaviors, actual vs. expected dosage form dissolution behavior affect the selection and design of appropriate mechanisms for creating CR dosage forms.

Solubilities

Identifying a suitable mechanism for creation of CR or applying a DS to a proposed CR mechanism may depend upon a DS having suitable solubility vs. pH or in pharmaceutical solvents. pH-solubility data can also be used to estimate the pKa of a DS in the absence of more reliable titration methods, or as a supportive estimate of the results of titration methods.

The preferred range for evaluation is pH 1 to 14; however, the range pH 1 to 8 is adequate and critical because it provides insight relevant to gastro intestinal (GI) behavior. Two practical solubility methods have been used in our laboratories, equilibrium and trial. The equilibrium method requires multiple analyses over time to establish an exact value. It has added value because it can detect polymorphic behavior. Figure 2 presents hypothetical solubility vs. time profiles for a DS that exists as two polymorphs. The equilibrium solubility of the DS is that of the more stable polymorph. Not allowing sufficient time for equilibration would result in an over estimation of the actual equilibrium solubility of the DS.

Equilibrium Solubilities

The first example is a routine determination of the pH solubility profile of McN-5707 free base at 25°C (Table II). There were no signs of polymorphic behavior. The data show that the pH range 1 to 8 is adequate for the characterization of this DS.

The second example is related to the investigation of potentially less soluble forms of linogliride (Fig. 3) for development of a CR line extension. Linogliride fumarate was in development as an immediate release (IR) dosage form to treat Type 2 Diabetes. Its solubility over the pH 1 to 8 range exceeds 150 mg/mL (Table III). The free base and four salts, pamoate, p-hydroxybenzoate, 3-hydroxy-2-naphthoate and the 1-napsylate, were prepared and their solubilities vs. pH were determined (Table III).

The solubilities of the four new salts are appreciably lower than the fumarate and the free base and meet the initial requirement of reduced solubility. Interestingly, the solubility of the 1-napsylate salt is independent of pH, and might provide zero-order release.

Trial Solubility

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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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