How to Successfully Utilize ASDs for Drug Delivery of Insoluble Drugs
Amorphous solid dispersion (ASDs) have grown exponentially since the late 1990s. The rise is due, in part, to the high percentage of poorly water-soluble compounds in drug pipelines. Availability of new large-scale manufacturing technologies are factors, as well.
A few new ASD products manufactured by various technologies have gained marketing approval this century. ASDs are still not fully utilized in drug delivery of drug candidates in clinical and commercial stages due to lack of full understanding of solid dispersion properties and reliable prediction of product scale up, stability, and in-vivo performance.
Contract development and manufacturing organizations (CDMO) who understand ASDs and their relationship to the downstream product scale up, stability, and in-vivo performance can prove to be invaluable partners. They can successfully utilize ASDs for drug delivery of insoluble drugs in early development and commercialization of human drugs in a timely and cost-effective manner.
Methods to Improve Absorption
Absorption of oral administrated solid dosage forms into the systemic circulation involves three factors. Dosage form disintegration, drug dissolution, and drug permeation across intestinal cell membranes into the systemic circulation all affect drug absorption.
For many poorly water-soluble drugs, especially the BCS II compounds, drug absorption is often limited by the drug dissolution rate from the dosage forms (kd<<ka). The maximum drug plasma concentration (Cmax) and time to reach the Cmax for this type of poorly water-soluble drug is dictated by the dissolution rate of the drug from the dosage form. Additionally, the fraction of drug absorbed will 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 reducing particle size to the micron or nanometer level. It can be done by increasing the hydrophobic drug wettability, whereas improvement in the solubility can be achieved by polymorph/salt form selection, complexation, solubilization, pro-drug, micro-emulsion, amorphous formation, and solid dispersion. Because the potentially increased apparent solubility can exceed 1000-fold as a result of amorphous formation, ASDs may improve the bioavailability of BCS II and IV compounds to an acceptable level without redesign of the molecular structure according. This is based on maximum absorbed dose (MAD) model:
Amorphous Materials Instability
One main hurdle with ASD commercialization is physico-chemical stability. Due to the inherent high free energy state of amorphous materials compared to crystalline, they have a high degree of supersaturation. Therefore, they have a high apparent solubility that results in high dissolution rates.
For the identical reason, the thermodynamic driving force for recrystallization to a lower energy physical form is high, which compromises stability and dissolution rate. ASDs have high entropy, enthalpy, and thermodynamic-free energy compared to their crystalline form. Because the stability of the dosage form will be determined by the amorphous API drug, good physical chemical characterization and accurate prediction of amorphous drug stability are essential to ASD success.
Most low-molecular-weight pharmaceutical drugs with 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) to stabilize and inhibit the amorphous drug from crystallization at its solid or aqueous states. Adding stabilizing agents into the multiple-component amorphous system will optimize the stability of the amorphous drugs, as well as improve the functionality and handling of the amorphous dosage form.
To leverage the higher solubility of amorphous solids and to mitigate physical instability risks, drug development teams must understand molecular structure of solid dispersions. Their relationship with the physical-chemical properties is for development of stable ASDs. Drug-polymer miscibility and the solid solubility of the crystalline drug in polymeric matrices important to ASD physical stability. Understanding these two properties will help select an appropriate polymer and determine an optimal amorphous drug-loading level for rational design of a stable ASD formulation.
Figure 1 shows a typical phase diagram of a two-component solution system exhibiting a miscibility gap (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.
Phase separation may follow two distinct mechanisms called nucleation and growth, and spinodal decomposition, depending on the location of the region. Nucleation and growth is 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.
Homogeneous, Molecular Mixture of Drug and Polymer
If treating the ASD as a solution system, the drug and polymer forming an ASD should be miscible to form a stable, homogeneous, molecular mixture of drug and polymer. At minimum, 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. Subsequent perturbation, such as temperature or concentration fluctuations, will cause recrystallization of the metastable amorphous drug 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 an amorphous drug in the solid dispersion system.
Re-crystallization of an amorphous drug within a solid dispersion can be significantly inhibited or reduced due to:
♦ Increase in the glass transition temperature
♦ Decrease in drug molecular mobility
♦ Drug-polymer interactions
♦ Increase in critical crystallization energy barrier by a reduction in the thermodynamic driving force
♦ Interference with the molecular recognition process for recrystallization.
All stabilization mechanisms require drug-polymer mixing and interactions at the molecular level. When phase separation happens for a drug-polymer amorphous system, the polymer has limited impact on the stability of the amorphous drug present in the drug-rich phase.
Based on thermodynamic phase separation theories, an ASD should be prepared. It should be done 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 the 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. In this scenario, a fraction of drug might be present in the metastable amorphous form.
Developing and Scaling Up of Formulations
The process flow of ASD formulation development consists of the following steps:
- Formulation screening
- Selection of polymer based on results from first step
- Stability testing and prediction of long-term stability
- Bio-pharmaceuticals evaluation in-vitro and in-vivo
- Selection of manufacturing method for ASDs
- Process development and scale up for final dosage form
- Characterization of the dosage forms
Various ASD dosage forms may be chosen, depending on the development stage. 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 on, a market formulation present as a capsule or a tablet form is desired to avoid a costly PK bridging study before transition into a Phase 3 pivotal human study (Table 1).
It’s critical for a CDMO team to choose a robust stable formulation and consider the scale-up effects at the early development stage. Spray-drying is well-established and widely used for transforming formulation in liquid into dry powdered forms. A spray-drying manufacturing process consists of five steps as shown in figure 2.
The temperature and evaporation rate at the inlet and outlet of the spray dryer can control the micrometrics properties of spray-dried solid dispersion powder. Phase separation of drug and polymer can be prevented by rapid removal of solvent from the droplets of the spray solution and subsequent rapid solidification of the droplets.
Hot-melt extrusion and liquid-melt filling technologies for encapsulation of melt solid dispersions into hard capsules are alternatives for solid dispersions. Manufacturing of the 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.
Three Scale-up Process Parameters
CDMOs need to focus on three critical process parameters 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 significantly impact the atomization of droplets that result in different ASD particle size distribution.
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.
Contact us to learn how we can be your CDMO for complex injectables for early phase studies.
This Formulation Forum was originally published on Drug Development & Delivery.
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