Salts and Polymorphs in Pharmaceutical Development

by Robert A. Carlton

Introduction
Importance of Solid State
Drug Substance solid properties affect Drug Product performance. Regulatory Agencies require the study of and control of solid state properties. Different solid state forms can be patented.

Effects on Drug Product

The solid state form of drug substance can affect the following drug product properties: Bioavailability Manufacturing Stability

Regulatory Agencies
Regulatory agencies require the study of and control of drug substance. To ensure that the drug substance used in the clinical studies is the same in the drug. They view control of the solid state form as evidence for good manufacturing controls.

Patents
Each solid form of a pharmaceutical can be patented. It is, then, critically important that the company developing the drug know all of the forms.

The Problem
One of the continuing scandals in the physical sciences is that it remains in general impossible to predict the structure of even the simplest crystalline solids from a knowledge of their chemical composition.
Maddox in 1988 Nature Editorial

Solid State Forms

Organic chemicals crystallize in a variety of ways: salt, free acid or base polymorphs hydrates solvates non-crystalline solid (amorphous)

Polymorphs
It is a surprising fact of nature that elements and molecules can crystallize in different ways. The different crystal forms are termed polymorphs. Example: acetaminophen

Acetaminophen Polymorphs

Acetaminophen Polymorphs

Properties of Polymorphs
Since polymorphs have different crystal forms, they also have different physical properties. Different polymorphs have been found to have different human bioavailabilities.

Properties Affected by Polymorphic Form

Preclinical Studies
Objectives
Salt form decision Form discovery studies

Preclinical Studies
Limitations
limited sample quantities non-optimized synthesis non-ideal purity poor crystallinity

Typically the emphasis at this stage is on salt characterization

Investigated Properties
Crystallinity Solubility / dissolution Hygroscopicity Biological activity / toxicity Stability

Preclinical Studies

Solid State Characterization Techniques Polarized Light Microscopy (PLM) X-ray Powder Diffraction (XRPD) Differential Scanning Calorimetry(DSC) Thermal Gravimetric Analysis (TGA) Water Vapor Absorption (WVA) Vibrational Spectroscopy (IR, Raman)

Preclinical Studies

DSC and TGA Results

Preclinical Studies
Salt Screening
Salt Screening is often conducted by both automated and manual methods In either case, hits require scale-up for analysis and characterization

Preclinical Studies
Form Screening
Variety of solvents - different classes Variety of crystallization schemes In either case, scale-up and characterization required

Preclinical Studies
Decision Criteria
Final dosage form Initial human trial dosage form Salt / form options Commercial importance

Form Decision Objectives

Discover and develop optimum form for pharmaceutical development
Assume that choice of salt, solvate, anhydrate etc. has been made The polymorphism must be investigated

Clinical Studies

Generally, the optimum polymorph is the thermodynamically stable one at room conditions

Polymorph Relationships Only one polymorph will be stable at atmospheric conditions. All others are metastable and will tend to convert to the stable one. It is important, therefore, to know which of the polymorphs is stable at atmospheric conditions.

Clinical Studies

Polymorph Relationships
It often is not easy to predict the stable polymorph. We must determine whether any pair of polymorphs have an enantiotropic or montotropic relationship.

Clinical Studies

Monotropy Vs Enantiotropy
For monotropic polymorphs, the high melting form will be the stable one at atmospheric conditions. For enantiotropic polymorphs, the low melting form will be the stable one.

Clinical Studies

Phase Relationships of Enantiotropic / Monotropic Polymorphs

FORM RELATIONSHIP
Evidence for Enantiotropy
Heat of Fusion Rule High melter has lower heat of fusion. (Form I - M.P. 154 0C, 11.2 kcal/mole; Form II M.P. 158 0C, 10.3 kcal/mole) Solubility High melter has greater equilibrium solubility at room conditions. Solution Phase Transformation In a saturated solution at room conditions, the high melter converts into the low melter.

Conclusion
The solid state form of the drug substance has important implications both for the use and sale of the potential drug.

Bibliography
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Bibliography
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DEFINITIONS
POLYMORPHS Solids having the same chemical structure but different geometrical packing. SOLVATES Solids having same chemical structure but with the inclusion of solvent. HYDRATE Solvate with water as the solvent. SALTS Ionic molecular solids.

DEFINITIONS
PSEUDOPOLYMORPH, PSEUDOMORPH Terms of uncertain definition. Can refer to solvates or to desolvated solvates. DESOLVATED SOLVATE A solid with the solvent removed, but leaving the same packing arrangement as the original solvate. HABIT The external shape of the crystal. FORM, MODIFICATION Umbrella terms referring to polymorphism and solvation, sometimes to habit.

DEFINITIONS
TRANSITION TEMPERATURE Temperature at which the Gibbs free energy of two polymorphs is the same. MONOTROPIC POLYMORPHS The transition temperature lies above the melting temperatures, higher melting form is the more stable at room temperature, two forms cannot be interconverted in solid state. ENANTIOTROPIC POLYMORPHS The transition temperature lies below the melting temperatures, lower melting form is the more stable at room temperature (if transition between RT and MP), two forms can be interconverted in solid state.