STABILITY OF SOLID DISPERSION SYSTEMS (P1)

Solid dispersion systems (SDS) are among the most effective strategies for improving the solubility and bioavailability of active pharmaceutical ingredients (APIs). However, SDSs are prone to instability, which can adversely affect their quality and therapeutic efficacy. This article analyzes the mechanisms and factors influencing the stability of SDSs.

1. Instability of Solid Dispersion Systems

1.1. Types of Instability:

• • Amorphous – amorphous phase separartion (AAPS): The API and polymer may separate into distinct phases, forming regions enriched with API or polymer. These regions are more prone to crystallization, negating the solubility benefits of SDS.

• • Crystalization: APIs in the amorphous state tend to revert to their more thermodynamically stable crystalline form over time, significantly reducing solubility and bioavailability.

1.2. Causes of Instability:

• • Thermodynamic Instability: The amorphous state has higher free energy, driving the system toward a lower-energy crystalline state. While crystallization stabilizes the thermodynamics, it significantly decreases API solubility.
  • Molecular Mobility: At elevated temperatures or humidity levels, API molecules become more mobile, increasing the likelihood of nucleation and crystal growth. Molecular mobility includes: α-Relaxation (Involves the coordinated motion of the entire molecule, typically occurring at temperatures above the glass transition temperature (Tg)) and β-Relaxation (Involves localized motion within parts of the molecule (e.g., specific atoms or bonds) and typically occurs at temperatures below Tg).

2. Factors Influencing Stability

The following diagram summarizes the factors affecting the instability of SDSs

3. API Structural Factors

After dissolving an API to the molecular level (e.g., via solvent evaporation or melting), the API can be transformed into an amorphous state upon rapid cooling, thereby avoiding crystal nucleation. Two key concepts are central to this transformation:

• • Glass Forming Ability – GFA: Defined as the ease with which an amorphous state can be achieved by cooling the liquid API (molecularly dissolved). The minimum cooling rate required for this process is termed the critical cooling rate, often used as an inverse measure of GFA. The critical cooling rate is determined using a time-temperature-transformation (TTT) plot.
  • Glass Stability – GS: Refers to the resistance of the amorphous API to recrystallization upon reheating from the amorphous state through Tg into the supercooled liquid state. GFA and GS are often interrelated; the ease of forming an amorphous state can indicate the duration for which this state can be maintained.

Research indicates that molecular weight and the free energy difference are critical factors influencing the GFA/GS and stability of an API:

• • High Molecular Weight and Rotational Flexibility: APIs with higher molecular weights and a large number of rotatable bonds require more time to arrange into favorable positions for nucleation and crystal growth.
  • Gibbs Free Energy Difference: The larger the free energy difference between the amorphous and crystalline states, the more spontaneously recrystallization occurs.

In addition to these factors, the glass transition temperature (Tg) and molecular mobility of an API are critical for stabilizing the amorphous solid dispersion (ASD) state, as explained below:

The following diagram illustrates the states of APIs (liquid – molecularly dissolved API; solid – crystalline or amorphous API) and the relationship between these states based on temperature and enthalpy.

• • Above Tg: API molecules can rotate relatively freely, enabling α-relaxation (coordinated molecular motion). This relaxation involves the movement of many API molecules in a coordinated manner.
  • Below Tg: Molecular mobility and relaxation processes of APIs are significantly slower. Molecules have limited freedom to rotate, and coordinated relaxation cannot occur. Secondary relaxations (often termed β- or γ-relaxations) may occur at temperatures below Tg. These secondary relaxations involve localized molecular motions, including intramolecular reorientation.

4. Factors Related to the Carrier (polymer)

4.1. Structure and Glass Transition Temperature of polymer

Many polymers possess high glass transition temperatures (Tg), making them effective as anti-plasticizers in polymer-drug mixtures. The Tg of a solid dispersion system, where the drug and polymer are molecularly dissolved into one another, is higher than the Tg of the active pharmaceutical ingredient (API) but lower than the Tg of the polymer.

Polymers with higher molecular weights exhibit higher Tg values as they require greater thermal energy to initiate α-relaxation due to increased viscosity. Commonly used polymers in the preparation of amorphous solid dispersions (ASD), such as HPMC, HPMCAS, and PVP, typically have Tg values exceeding 100°C.

4.2. Interaction and Miscibility with the Drug

The polymer’s ability to form stable interactions with the API is a crucial consideration during the development of ASDs, as it can reduce molecular mobility and prevent drug recrystallization.

• • Polymers capable of forming hydrogen bonds with the API result in ASDs with higher physical stability compared to those with weaker or no hydrogen bonding capabilities.
  • Highly compatible polymers can create strong interactions with the API, reducing the system’s free energy and delaying crystallization. Strong API-polymer interactions promote the formation of a single-phase system, with the API molecularly dispersed within the polymer matrix, enhancing the thermodynamic stability of the ASD. Polymers with high viscosity and high Tg values further limit API molecular mobility, improving stability.

The miscibility of the API and polymer is often measured as the solubility of the amorphous API (rather than its crystalline counterpart) in the amorphous polymer. The degree of miscibility between the polymer and the API is an important determining factor, influencing the ability to achieve a stable maximum API loading at a given temperature.

The threshold is referred to as the amorphous API-polymer miscibility limit. The greater the miscibility, the higher the amorphous API load that can be incorporated into the polymer matrix before saturation. Beyond this limit, crystallization occurs, reducing ASD stability.

If the API and polymer have limited miscibility, achieving an effective ASD formulation may necessitate a high polymer concentration, leading to increased tablet weight and reduced patient convenience.

4.3. Moisture Content in Polymer Materials

The hygroscopic nature of polymers significantly impacts the physical stability of ASDs. Water acts as a potent plasticizer, and even a small amount, when molecularly mixed with the polymer, can lower its Tg.

Moreover, the polymer’s moisture absorption capacity influences the amount of water absorbed by the ASD under high-humidity conditions. Water absorption can alter the system’s structure; water molecules may replace the API within the ASD by forming hydrogen bonds with the polymer, potentially leading to phase separation. This results in two distinct regions: one API-rich and one polymer-rich, each with separate Tg values. When this phase separation is caused by water, the process is called moisture-induced phase separation (MIPS). The presence of MIPS can reduce the stability and efficiency of the ASD, and negate the advantages of the original system.

4.4. Formulation Factors

The ‘miscibility’ of an API and polymer is generally understood as the solubility of the amorphous API in the amorphous polymer.

Zones 1 and 3 describe thermodynamically stable and supersaturated amorphous solid dispersions (ASDs), respectively. In formulating ASDs, classification into Zone 1 should be aimed at since recrystallization is thermodynamically unlikely. However, this may result in drug loadings that are too low, rendering the formulation unfeasible for final dosage form development.

5. Manufacturing Processes Factors

5.1. Methods for Preparing Solid Dispersion Systems

Different ASD manufacturing techniques allow varying degrees of miscibility between the polymer and API during the amorphization process. For example, spray-drying often achieves higher drug loads compared to mechanical milling. This is because, during spray-drying, the polymer and API are molecularly dispersed in solution, facilitating stronger interactions compared to the mechanical milling process.

5.2. Residual Solvents in Solvent-Based Methods

While spray-drying can achieve greater miscibility between polymer and API, it is essential to eliminate residual solvents to maintain the physical stability of the ASD and comply with regulatory requirements for the final product.

5.3. Compression Process for Final Dosage Form

The tablet compression process can alter the original structure of the ASD. For instance, the ASD of naproxen in PVP (30% w/w) has been observed to undergo phase separation at compression pressures exceeding 367 MPa. This leads to the formation of two distinct phases, visible as two separate Tg values, compromising the stability and efficacy of the formulation.

6. Storage Conditions

Nhiệt độ bảo quản ASD là yếu tố quan trọng đối với độ ổn định. Tuy nhiên, việc giảm nhiệt độ bảo quản của một ASD có thể nên quá bão hòa và dễ bị tái kết tinh.

Due to their larger surface area, ASDs are more prone to absorbing moisture from the air compared to their crystalline counterparts. Additionally, polymers selected for ASD formulation often exhibit hygroscopic properties, which increase molecular mobility and, consequently, the likelihood of API crystallization.

Reference:

Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic, Kinetic and Environmental Aspects