The paradigm shift in the drug discovery process from wet chemistry to combinatorial chemistry and high throughput screening since the mid 1990s, has prompted the development scientists to evolve contemporary and innovative formulation techniques. Improvement of oral drug bioavailability remains a prime area of work to successfully traverse the potent, lipophilic and high molecular weight drug candidates through the development phase. Oral drug bioavailability is ruled by the solubility and permeability profile of the drug, with former being more accessible to enhancement. The approach of 'solid-state manipulation' for active pharmaceutical ingredients investigates alternative solid forms for pharmaceutical advantage ranging from 'solubility' to 'manufacturability' improvement. Amongst the polymorphs, pseudo-polymorphs, and amorphous form, the latter has come into limelight as it can deliver the maximal solubility advantage for a solid material.
Amorphous materials also termed as 'glasses' or 'disordered systems' are characterized by a short-range molecular order, as compared to the long-range three-dimensional arrangement of unit cells present in the crystalline counterparts. Thermodynamically, amorphous form is the most energetic solid state of a material with 'excess' enthalpy, entropy and free energy. This manifests as the high 'kinetic' solubility of the amorphous form, leading the increased rate of drug absorption and thus increased bioavailability. The enhanced bioavailability can reduce the total dose required to elicit the pharmacological response. Amorphous solids on aging convert to their lower energy stable crystalline state and this physical instability entails some critical considerations for their application in drug delivery. Drug-carrier based solid dispersions have been successfully used to stabilize a wide array of amorphous drugs. The stabilizing mechanism involves restricting the molecular motions in the glassy state through dilution effect, anti-plasticization effect and specific drug-carrier molecular interactions. These solid dispersions then need to be converted to final dosage forms, which involves various challenges during processing and performance stages. The proceeding sections discuss the issues, that should be given due consideration while developing amorphous solid dispersion based dosage forms.
Critical consideration for product development
Dosage form selection for a pharmaceutical active is done based on its physico-chemical properties, disease condition, the target site and delivery requirements. For a drug its macroscopic properties are derived from its basic molecular level arrangements. Amorphous active pharmaceutical ingredient (API) should be characterized by properties such as glass transition temperature, molecular mobility, fragility, and devitrification kinetics. These parameters also indicate its thermodynamic and kinetic 'stability' and 'performance' in pharmaceutically relevant environmental conditions. Systematic protocol to screen the response of amorphous material over the expected range of conditions to be experienced can provide an assessment of its 'developability' potential.
Solid state 'stability' and 'solubility' of amorphous API
Solubility: Theoretically, amorphous systems being the most energetic solid form for a substance will provide the maximum apparent solubility benefit. The increase in solubility leads to increased driving force for dissolution and thus enhanced bioavailability. For a better evaluation of the in-vitro and in-vivo dissolution advantage, the 'kinetic' solubility should be studied as a function of bio-relevant conditions of pH, ionic strength, and surfactant concentration.
Glass transition: The glass transition is the prime parameter that differentiates an amorphous state from a crystalline one. Glass transition temperature (Tg) is the region at which material on cooling, changes from a supercooled liquid or rubbery state to the amorphous glassy state. Usually, Tg lies in the region approximately 2/3 to 4/5 of crystalline melting point (Tm). Higher Tg value indicates better stability of the amorphous system. The safe storage conditions being recommended as Tg - 50K where the molecular mobility is considered to be negligible. Water present in amorphous solids acts a potent plasticizer and reduces Tg of the material, hence a quantitative determination of Tg shift w.r.t. moisture content becomes a critical information for processing amorphous drugs.
Molecular mobility: The rate of molecular diffusions in different material states can be ranked as liquid > rubber > glass > crystal. Molecular motions in a crystalline solid are restricted to vibrational motions, however amorphous solids due to lack of long range order can also undergo translational motions (i.e. diffusion of molecules from one loci to another) and thus have higher molecular mobility. Molecular mobility changes with environmental conditions like increase in temperature results in higher mobility which further favors the crystallization process. The molecular mobility is typically non-exponential and the parameter mean relaxation time ( ) at temperatures above and below Tg is used to predict the required storage conditions for acceptable shelf life. Fragility: Amorphous drugs can be classified as strong or fragile glass formers based on temperature dependence of molecular mobility. Materials showing fragile behavior indicate greater tendency to devitrify over the shelf life period and show large change in molecular mobility near Tg.
Devitritification kinetics: In the pharmaceutical development phase the active would be exposed to varied condition of external stress that could be thermal, mechanical and/or chemical. Some of them such as moisture, temperature and compression pressure have been reported to be detrimental to physical stability of amorphous form and can trigger the crystallization process. Hence determination of the crystallization onset as a function of applied stress can provide valuable inputs for formulation/process selection and prediction of long term stability of the dosage form.
Challenges for amorphous drug delivery
With the greater interest revived in the amorphous system as a means to improve delivery of poorly water insoluble drugs significant opportunity still exist in better understanding and engineering of custom amorphous pharmaceutical materials.
Quality: Standardization of active material is essential as the solubility performance is dependent on its thermodynamic and kinetic state, which can further have biopharmaceutical consequences. Material quality markedly depends on the method of preparation and process parameters such as heating and cooling rates, maximum temperature used, and holding time. Quantitative characterization tools: Analytical techniques for quantitative characterization of amorphous drug materials for solid form purity are less established. Amorphicity is most commonly demonstrated by the absence of crystallinity. All the more, detection of solid form reversion in a multi-component dosage form remains an arduous task.
Performance prediction: Oral dosage forms prepared from solid drug dispersions have been reported to show non-disintegrating behavior. Despite inclusion of super-disintegrants, tablets show poor disintegration and drug dissolution is mainly by surface erosion. The reduced dissolution could be due to the high polymeric material in amorphous dispersions. Also it has been observed that typically amorphous solids undergo rapid surface devitrification when brought in contact with aqueous environment resulting in formation of an outer layer of crystallized material that hinders wetting of the inner core.
Manufacturing processes: Molecular solid dispersions can be prepared through processes such as fusion/melt method, rapid solvent evaporation method (spray drying, freeze drying), hot melt extrusion and supercritical fluid technology. Melt methods are less applicable to thermolabile drugs and carriers, and the solvent based methods involve time consuming issues of appropriate solvent system selection and its removal from the product. Further manufacturing processes for incorporating the amorphous systems into dosage form have to be identified. Solid drug dispersions being hygroscopic and tacky in nature may not be well-suited for the conventional unit processes such as pulverization, sieving, flow and compression.
Formulation design and process alternatives
Formulation additives can impact the solid state stability and overall performance of an amorphous pharmaceutical dosage form. At the initial stage and during shelf life, excipients can be a prime source for the 'free' unbound water which can mediate the solid-solution phase transformations. Excipients based on their material properties can interact with amorphous API to catalyze degradation or stabilize against recrystallization. Hence the drug-excipients compatibility studies performed in the preformulation phase should also evaluate the physical stability of amorphous drug. As the carriers in solid dispersions are typically hygroscopic, large molecular weight viscous materials, the carrier selection and drug-carrier ratio in solid dispersions is critical to developability of the material. Incorporation of crystallization inhibitors; use of non-hygroscopic excipients and channeling agents to improve dispersion; and additives that act as protectants from process mediated stress can result in optimal delivery of amorphous drugs.
Amorphous drugs/solid dispersions may not be amenable to certain manufacturing processes used to formulate conventional dosage forms of tablets and capsules. The high shear wet granulation process is not suited for majority of the amorphous systems as the granulating fluid (water, non-aqueous solvents) acts as plasticizer and spontaneously induce the reversion process. Also the thermal stress experienced during drying process can affect the physical stability. Thus dry processes such as direct compression and dry granulation would be more preferred. While selecting the dry granulation process, material stability to the applied mechanical stress during compaction/slugging should be evaluated. Further, the final compression step can be avoided by use of capsule dosage form in place of tablets. In some cases, the moisture sensitive core can be protected by applying polymeric seal-coat. The process and dosage form selected should meet two major objectives first, to maintain the performance advantage of the amorphous solid drug dispersion in finished dosage form and second, to subject the material to minimal stress conditions and thus maintain its physical stability. Newer approaches of formulating amorphous drugs/solid dispersions have been suggested and some of the industrially scaled up techniques are discussed below:
Solid drug dispersion layering using fluidized bed coating system: Drug-carrier solution prepared in suitable solvent is coated on to sugar spheres with controlled drying by closed Wurtser process. The solid solution coated beads can then be either encapsulated or compressed into tablets.
Hot-melt extrusion: This is a solvent free process wherein the drug-carrier blend is mixed, melted, kneaded and then extruded to get granules, pellets, powder or films. The drug dissolves in the carrier during mixing and remains as a molecular dispersion in the hardened polymer on cooling after extrusion.
Direct capsule filling: The process exerts least shear with the drug dispersed in molten carrier filled directly into hard gelatin capsules at temperatures below 70 ºC. The material on cooling to room temperature solidifies into a plug. Usually surfactants are added to this system to promote dispersion of fine colloid particles and avoid formation of drug rich layer on the surface. Supercritical fluid technology: Microparticles of solid dispersion are prepared by rapidly varying the solvent strength in a closed system with supercritical fluid as carbon dioxide (CO2) above its critical temperature. The process can also be solvent free where drug melt and carrier saturated with CO2 is rapidly cooled by abatic expansion of CO2 to precipitate the solid dispersion as microparticles.
Some commercialized drug products based on above technologies are Gris-PEG tablets (Novartis) - griseofulvin in polyethylene glycol (PEG); Cesamet capsules (Lily) - nabilone in polyvinylpyrrolidone; Prograf capsules (Astellas Pharma) - tacrolimus in hydroxypropyl methylcellulose (HPMC); and Sporanox capsules (Janssen Pharmaceutics) - itraconazole in HPMC and PEG 20,000 matrix.
Advantages of amorphous systems
Amorphous drug delivery when compared to other solubility enhancing techniques can provide unique advantages. Use of surfactants and cyclodextrins for enhancing solubility of water-insoluble drugs is limited due to related toxicity issues. Nanoparticulate drug delivery systems for bioavailability enhancement are considered as combination products and are shrouded by characterization, safety and environmental issues. In comparison, the high energy amorphous solid form is a mere different physical state of single chemical entity with no chemical modifications and thus holds no toxicity and safety concerns. Also majority stabilizers/crystallization inhibitors used for amorphous drugs are GRAS (generally recognized as safe) listed pharmaceutical excipients and are safe for oral intake. This gives amorphous systems distinct advantage and it emerges as an economical and safer approach for faster drug product approvals. Amorphous drug delivery can be applied to development of new chemical entities, to improve delivery of old molecules with poor biopharmaceutical properties and also attracts the generic drug companies as a viable means to circumvent patented innovator products and add to the intellectual property portfolio of pharmaceutical companies. The industrial scale production of amorphous solid dispersions can be most efficiently done in chemical plant facilities which are equipped to handle large solvent based processes. Integration of manufacturing of amorphous drug systems with bulk drug synthesis would also accelerate their industrialization. This can be a potential area of expansion for India's bulk drug industry, with its established expertise and knowledge base in chemical processes.
( Vibha Puri is research scholar and Dr Arvind K Bansal is associate professor in the department of Pharmaceutical Technology (Formulations) at National Institute of Pharmaceutical Education and Research (NIPER ) Punjab.)