FORMULATION FORUM - Understanding of Amorphous Solid Dispersions & Their Downstream Development

INTRODUCTION

Amorphous solid dispersion (ASDs), in which drug is amorphously dispersed within polymer(s), would significantly increase drug dissolution rate by a simultaneous increase in local aqueous solubility as a result of amorphous formation and excipient solubilization effects, and in dissolution surface area by a reduction in particle size to the minimum level. Amorphous solid dispersions have experienced an exponential growth since the late 1990s. This phenomenon is partially attributed to the current need to address the high percentage of poorly water-soluble compounds in drug pipelines and the availability of new large-scale manufacturing technologies, eg, spray dried, liquid (melt)-filled capsules and hot-melt extrusion. A few new ASD products manufactured by various technologies have gained marketing approval since 2000. However, due to the lack of full understanding of solid dispersion properties and reliable prediction of product scale up, stability, and in-vivo performance, ASDs are still not fully utilized in drug delivery of drug candidates in clinical and commercial stages.

MECHANISM IN IMPROVING ABSORPTION

Drug absorption process of oral administrated solid dosage forms into the systemic circulation involves dosage form disintegration, drug dissolution, and drug permeation across intestinal cell membranes into the systemic circulation.

The slowest step described earlier determines the rate of drug absorption process.

For many poorly water-soluble drugs, especially the BCS II compounds, the drug absorptions process is often limited by the drug dissolution rate from the dosage forms (kd<<ka). As a result, not only the maximum drug plasma concentration (Cmax) and time to reach the Cmax for this type of poorly water-soluble drug will be dictated by the dissolution rate of drug from the dosage form, the fraction of drug absorbed will also be affected by the drug dissolution rate if the time required for complete dissolution is longer than the transit time of the dosage form at the drug absorptive sites.

The effective dissolution surface area can be increased by particle size reduction to the micron or the nanometer size range or by increasing wettability of the hydrophobic drug, whereas improvement in the solubility can be made possible by polymorph/salt form selection, complexation, solubilization, pro-drug, micro-emulsion, amorphous formation, and solid dispersion. Because the apparent solubility could be potentially increased more than 1000-fold as a result of amorphous formation, ASDs could potentially improve the bioavailability of BCS II and IV compounds to an acceptable level without redesign of the molecular structure according to the maximum absorbed dose (MAD) model (Equation 1).

INTRINSIC INSTABILITY OF AMORPHOUS MATERIALS

One of the major hurdles with commercialization of ASDs are their physico-chemical stability and difficulty in their prediction. Due to the inherent high free energy state of amorphous materials compared to their crystalline counterpart, they bring the advantage of a high degree of supersaturation and therefore a high apparent solubility that result in high dissolution rate. However, due to the same reason, the thermodynamic driving force for recrystallization to a lower energy physical form is high, which compromise stability and dissolution rate. The heterogeneity of ASDs make the predictability of physico-chemical properties of solid dispersion, such as solid state structure, dissolution mechanism, stability on storage, and the in-vitro/in-vivo correlation, difficult. ASDs have high entropy, enthalpy, and thermodynamic free energy compared to their crystalline form. Because the stability of the dosage form will be mainly determined by the amorphous API drug itself, good physical chemical characterization and accurate prediction of stability of the amorphous drug are the keys to the success of ASDs. Furthermore, because most low-molecular-weight pharmaceutical drugs having a Tg of <75°C recrystallize out readily during stability or in-vivo dissolution, it is often necessary to add excipients, particularly polymers, to form a multiple-component amorphous system (ie, ASD) in order to stabilize and inhibit the amorphous drug from crystallization at its solid or aqueous states. The introduction of stabilizing agents into the multiple-component amorphous system would not only optimize the stability of the amorphous drugs, but also improve the functionality and handling of the amorphous dosage form, eg, a reduction in stickiness, powder flow properties, moisture scavenging and protection requirement in storage conditions, and packaging, etc.

THERMODYNAMICS OF AMORPHOUS SOLID DISPERSIONS

To take advantage of the higher solubility of amorphous solids and to mitigate risks associated with physical instability, an understanding of molecular structure of solid dispersions and their relationship with the physical-chemical properties is essential for development of stable ASDs. Two of the physical properties that are of especially important to physical stability of ASDs are the drug-polymer miscibility and the solid solubility of the crystalline drug in polymeric matrices. Miscibility refers to capability of mixing two liquids in any ratio without separation of two phases, whereas solubility is defined as “the spontaneous interaction of two or more substances to form a homogenous molecular dispersion.” An understanding of these two properties will help in selecting an appropriate polymer and determining an optimal amorphous drug-loading level for rational design of a stable ASD formulation.

According to thermodynamic theories, a typical phase diagram of a two-component solution system exhibiting a miscibility gap is illustrated in Figure 1. The phase diagram is divided into regions showing one-phase stable, and two-phase metastable and unstable phases. The binodal curve separates the stable homogenous phase from the two-phase regions, whereas the spinodal curve divides the two-phase region into a metastable and unstable phase. Phase separation may be induced by a temperature jump or a concentration fluctuation that causes the system to transition from the one-phase stable phase into the unstable regions. Depending on the location of the region, phase separation may follow two distinct mechanisms called nucleation and growth, and spinodal decomposition. Nucleation and growth happen when phase separation occurs inside the two-phase metastable region near the binodal line where the free energy change for phase separation is low. Because nucleation involves creation of a new surface, there is an activation energy barrier required for nucleation and growth. For a dispersion with a composition located within the spinodal region, the system that is unstable against any fluctuations in concentration will undergo phase separation via spinodal decomposition. Even though there is no thermodynamic energy barrier for spinodal decomposition, phase separation can be stopped or become extremely slow when the temperature is below the glass transition of the system.

If treating the ASD as a solution system, the drug and polymer forming an ASD should be miscible (located in the stable one-phase region) in order to form a stable, homogeneous, molecular mixture of drug and polymer, ie, amorphous solid solution. At the very least, drug and polymer should be miscible in their liquid/molten state. Otherwise, metastable drug-rich amorphous phases as well as polymer-rich phases will be present in the solid dispersion formed upon solidification, and any subsequent perturbation, such as fluctuations in temperature or concentration, will further cause recrystallization of the metastable amorphous drug present in the system. In general, it is believed the formation of a single phase as an amorphous solid solution is essential for the stability of amorphous drug present in the solid dispersion system. According to nucleation theories, the re-crystallization of an amorphous drug within a solid dispersion can be significantly inhibited or reduced by an increase in the glass transition temperature, a decrease in drug molecular mobility, drug-polymer interactions, an increase in critical crystallization energy barrier by a reduction in the thermodynamic driving force, or by interference with the molecular recognition process for recrystallization. All of the aforementioned stabilization mechanisms require drug-polymer mixing and interactions at the molecular level. When phase separation happens for a drug-polymer amorphous system, the polymer would have limited impact on the stability of the amorphous drug present in the drug-rich phase due to lack of the intimate interactions between the drug and polymer required for stabilization.

Based upon the same thermodynamic phase separation theories, an ASD should also be prepared preferably at a drug concentration below the solid solubility of its crystalline form, so that the dispersion system will fall within the one-phase stable region, and drug is homogeneously distributed within the solid matrix at a molecular level. Otherwise, when the amorphous drug loading is above its solid solubility for practical reasons, the system may become supersaturated and fall within the metastable two-phase regions. As a result, a fraction of drug might be present in the metastable amorphous form.

FORMULATION DEVELOPMENT AND SCALE UP

The process flow of ASD formulation development consists of the following steps:

1. Formulation screening (miscibility, stability, and dissolution)
2. Selection of polymer based on results from first step
3. Stability testing and prediction of long-term stability
4. Bio-pharmaceuticals evaluation in-vitro and in-vivo
5. Selection of manufacturing method for ASDs (spray dry, HME, liquid fill capsule, fluid bed process, co-precipitate, solvent evaporation, etc)
6. Process development and scale up for final dosage form
7. Characterization of the dosage forms
8. IVIVC

Different dosage forms of ASDs may be chosen depending on the stage of development. Early stage formulation prefers aqueous suspension or drug-in- bottle approaches that can be easily prepared by a Tox lab or by Clinical Pharmacology Unit from the ASD powder. From Phase 2 and onward, a market formulation present as a capsule or a tablet form is desired in order to avoid a costly PK bridging study before transition into a Phase 3 pivotal human study (Table 1).

It is critical to select a robust stable formulation and to consider the scale-up effects at the early development stage. Spray-drying is a well-established and widely used process for transforming formulation in liquid into dry powdered forms. In addition to hot-melt extrusion technology, liquid-melt filling technologies for encapsulation of melt solid dispersions into hard capsules are another alternative technology for solid dispersions. The manufacturing of this SD dosage form involves the dissolving of drugs in melted carriers and the filling of the solutions into hard gelatin capsules. Due to simplicity in the manufacturing processes and potential in significant improvement of bioavailability of poorly water-soluble drugs, solid dispersion systems by liquid-filled technology is an attractive option for development of insoluble drugs.

A spray-drying manufacturing process consists of five steps (Figure 2):

1. solution preparation containing the drug and excipients dissolved in solvent
2. atomization of the spray solution
3. primary drying of the atomized droplets in the spray chamber
4. collection of the ASD via cyclone
5. secondary drying to reduce the residual solvent to acceptable limits

Click image to enlarge

In the spray-drying process, not only can the micrometrics properties of spray-dried solid dispersion powder be controlled by controlling the temperature and evaporation rate at the inlet and outlet of the spray dryer, but also phase separation of drug and polymer could be prevented by rapid removal of solvent from the droplets of the spray solution and thereby rapid solidification of the droplets.

Three critical process parameters are the focus areas during scale-up: atomization, drying, and separation. DOE design can be explored to understand key spray-drying process parameters and their relationship to the critical-quality attributes (CQAs). Nozzle design and pressure may have significant impact on the atomization of droplets that result in different ASD particle size distribution. Because pressure nozzle commonly used in large-scale spray dryers generates broader particle size distribution, the sensitivity of drug dissolution and bioavailability as related to ASD particle size distribution should be evaluated early to ensure the formulation and process robustness. Higher inlet temperature and lower outlet temperature tends to result in faster evaporation rates and smoother surface of ASD particles.

SUMMARY

Understanding the properties of ASDs and their relationship to the downstream product scale up, stability, and in-vivo performance is critical to successfully utilize them for drug delivery of insoluble drugs in early development and commercialization of human drugs in a timely and cost-effective manner. u

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Jim Huang, PhD
Founder & CEO
Ascendia Pharmaceuticals
j.huang@ascendiapharma.com
www.ascendiapharma.com