BIOAVAILABILITY ENHANCEMENT – Overcoming Poorly Soluble Pharmaceutical Formulations With Hot Melt Extrusion
Solubility is an essential characteristic of active pharmaceutical ingredients (APIs), with profound effects on process and clinical development, formulation, and commercialization. Higher-solubility drugs dissolve more completely and are generally more bioavailable than low-solubility products; rate of dissolution also plays a key role in effective bioavailability.
Poorly soluble compounds disperse sparingly in the gut and are mostly excreted. Because poor solubility and inadequate bioavailability go hand in hand, solubility issues affect every stage of a drug’s development.
Estimates have varied over the years, but at least 40%, and as many as 70% of New Chemical Entities (NCEs) are considered poorly soluble in water, leading to low bioavailability, high intraand inter-patient response variability, and variable dose proportionality.1,2 When BCS Class II (high permeability, low solubility) and BCS Class IV (low permeability, low solubility) are combined, the percentage of poorly soluble NCEs is approximately 90%.2 Comparing these figures with the percentage for approved drugs, 30%, drug development is unmistakably trending toward molecules with poor solubility.
Increasing chemical complexity and molecular weight among candidate molecules, and a decreased reliance on soluble natural products as starting points for NCEs, are possible explanations for this trend. Some observers have noted that the “low hanging fruit” of candidate molecules with ideal physic-chemical properties has for the most part been harvested.
As solubility issues reach a critical stage at discovery and development firms, advanced formulation technologies for overcoming poor solubility are becoming essential for the continued productivity of innovators’ drug pipelines. Because poor bioavailability masks the true potential of development-stage drugs, advanced formulation is no longer an optional activity, but indispensible to the very success of NCEs.
In a recent study conducted on Catalent’s behalf by McKinsey and Co., top managers at development-stage pharmaceutical companies listed bioavailability enhancement as the most significant challenge in their drug delivery and formulation efforts.3 McKinsey identified especially acute needs for bioavailability enhancement of small molecule drugs, oral protein drugs, targeted delivery (particularly to the upper GI tract), and overcoming food effects. Additionally, in a recent industry survey, 41% of respondents reported bioavailability as a key challenge in their active pipeline development programs.4
SOLID DISPERSIONS & SOLUTIONS
Strategies for overcoming poor solubility and permeability are many and varied. Emulsification, micronization, nanoparticle APIs, complexation with liposomes or cyclodextrins, counter-ion modifications, and permeation enhancers each have their plusses and minuses, but all lack general application to the diverse chemical structures comprising poorly soluble drug candidates.
Solid dispersions and solid solutions are two generally applicable strategies for overcoming poor solubility. Pioneering work by Janssen Pharmaceuticals with Sporanox®, and Parke-Davis’ Rezulin, demonstrated that solid dispersions could play a role in ameliorating solubility issues through easily accessible formulation and manufacturing methods.
In solid dispersions, the drug and a soluble pharmaceutical-grade polymer matrix exist, co-mixed but in separate phases, with the drug either in crystalline or amorphous form. Solid solutions differ from dispersions as the two components combine, in a single phase, at the molecular level. By necessity, the drug concentration in a solid solution is lower than its saturation value for the particular polymer matrix, otherwise crystallization or aggregation of API would occur (phase separation).
Solid crystalline dispersions consist of the API in crystalline form dispersed within the polymer carrier. These occur when, for purposes of preserving drug substance stability, the processing temperature is lower than the drug’s melting temperature. Crystalline dispersions also arise through recrystallization of the API from a melt, or as an equilibrium state between crystalline and amorphous forms. When analyzed by differential scanning calorimetry, solid crystalline dispersions display separate temperature breaks for the polymer’s glass transition temperature (Tg) and the drug’s melting point.
Solid glassy dispersions are similar to crystalline dispersions except that in this case, both the polymer and drug exist in amorphous states. API is well-dispersed, but in a separate physical domain from that of the carrier. Analysis by differential scanning calorimetry shows separate Tg for drug and polymer. Because the amorphous API is held in clusters, such glassy dispersions are more likely than a solid solution to revert to the crystalline state.
Techniques for producing solid dispersions include solvent-based operations (eg, spray-drying, solvent casting, freezedrying) and techniques based on melting (spray congealing, melt granulation, and hot melt extrusion/HME).5
Solvent-based approaches involve dissolving the drug and polymer in an organic solvent, and removing the solvent to leave behind powder or granules. Because most drugs are hydrophobic, and most polymers hydrophilic, dissolution requires large volumes of solvent that raise issues of safety, energy usage, and disposal.
Of the three techniques, HME is the most versatile and generally applicable to poorly soluble drug candidates. HME creates pharmaceutical-polymer dispersions of quality comparable to solvent-based methods, but without the solvent.
In pharmaceutical formulations, HME is most often associated with solid dispersions, although solid solutions of high-energy amorphous API may be more effective as solubility enhancers.
Heating a crystalline API above its melting point produces a liquid which, upon cooling, often reverts to crystalline form. But, in certain situations, the drug enters an amorphous glassy state through a supercooled liquid phase. The temperature at which the super-cooled liquid is in equilibrium with the glass is the Tg. The glassy materials, in which the molecules are not ordered, is less energetically stable than the crystalline form. Consequently, amorphous materials processed in this way dissolve more rapidly than crystalline API.
However, in solid solutions, crystallization may become an issue if the storage temperature is less than 50 degrees lower Tg. The remedy is to employ a polymer matrix with a significantly higher Tg . This confers a higher, more suitable Tg on the solid solution, and hence a more stable formulation.
Overall, high-energy hot-melt extrudates based on amorphous API dispersions or solid solutions provide significant solubility advantages compared with crystalline drug, particularly in the case of true solid solutions. Because amorphous materials are of higher energy than the crystalline form, they dissolve more readily. Moreover, for solid solutions, their dissolution within the matrix at the molecular level results in the highest possible effective surface area, which promotes physiologic absorption as well.
Amorphous physical forms of common drugs carry caveats as well. Amorphous materials may be metastable, meaning they may spontaneously interconvert to the more thermodynamically stable crystalline form, leading to potential issues with drug product stability. Moreover, producing an amorphous form may still not provide suitable bioavailability for APIs that do not possess innate “druggable” solubility.
HME PROCESSING & EQUIPMENT
HME has been widely used in the polymers and food industries for more than 70 years. Pharmaceutical developers have only employed HME for the past 15 years. According to Crowley et al, the number of HME patents covering pharmaceutical applications rose steadily between 1983 and 2005, reaching approximately 25 patents per year.6 Germany, the United States, and Japan issued approximately three-fourths of those patents.
HME involves heating, mixing, compressing, and transporting a dispersion of APIs, plasticizers, surfactants, and other excipients within a suitable pharmaceuticalgrade polymer carrier, typically utilizing corotating twin screws with various pitch designs to achieve desired mixing and residence times in the various heating and cooling sections of the extruder.
Where single-screw extrusion is more common in polymer processing, twin screw extruders are the most common for processing pharmaceuticals as hot melt extrudates. Compared with single-screw machines, the twin-screw design provides better mixing of non-homogeneous systems (ie, drug and polymer), better control over melting temperatures, and easier addition of ingredients.
The three principal phases of the process are conveying, melting (occurring within the barrel), and shaping or extrusion. Residence time within the extruder typically ranges from about half a minute to 5 minutes. The mixture liquefies and emerges as a homogeneous liquid or semi-solid, which solidifies upon cooling.
Process parameters affecting the final formulation include screw diameter, spacing between the screws and the chamber wall, temperatures along the die assembly, and the screws’ pitch angles, rotation rate, and lengthto- diameter ratio.
Screw design strongly influences the properties of finished HME products. Screws provide both conveying and mixing by meshing through very narrow gaps, both between the co-rotating screws and between screws and extruder wall.
HME equipment is diverse in design and operation. One notable model type features multiple hoppers along the conveyingmelting- extrusion flow path to enable addition of ingredients during the melt processing. Another is multiple heating zones along the flow path to tailor heating regimens to the composition of various ingredients. Hot melt extruders can provide melting temperatures as high as 250ÂºC, although to ensure drug substance stability, processors avoid highly elevated temperatures. To ensure stability, an HME process should occur no higher than about 40ÂºC above the Tg of the polymer, which in turn is selected based on the API’s melting temperature among other criteria.
Because it is a continuous process with narrowly defined output quality attributes, HME represents an ideal manufacturing platform for implementation of Process Analytic Technology (PAT). Through this FDA initiative, manufacturers are encouraged to gain process understanding by identifying and controlling critical parameters in real-time or close to it. Appropriate measurement devices, such as near-infrared sensors positioned inline or at-line, can meet requirements associated with PAT for HME in ways that other pharmaceutical manufacturing operations cannot achieve.
Because hot melt extrudates exhibit unique thermodynamic properties, much may be learned from the thermal behavior. Calorimetry and thermogravimetric analysis are critical analytical techniques during HME processes. Other analysis methods adopted from both pharmaceutical development and materials processing include solid state NMR, liquid chromatography, scanning electron microscopy, particle characterization methods (eg, light scattering, sieving), and USP methods for batch release.
HME CARRIER MATRICES
HME formulations consist of a thermoplastic carrier, and may comprise further excipients, such as solubilizers, surfactants, or binders, such as gelucire, vitamin E TGPS, waxes, lipids, polyols, and alpha hydroxyacids, plasticizers (eg, polyethylene glycols, triethyl citrate), sugars, organic acids, complexing agents, biodegradable polymers, and combinations of these ingredients. Pharmaceutical-grade polymers are by far the predominating excipient.
Choice of polymer is crucial for imparting the desired characteristics to the final HME formulation. Typical carrier polymers include povidone, copovidone, hydroxypropyl and ethyl celluloses, acrylates, and most recently, a polymer with amphiphilic chemical structure, Soluplus.
The most important properties of the polymer matrix are Tg and melt viscosity, solubilization capacity, stability, and toxicity/regulatory status.7 The latter is critical as the matrix is present at very high doses relative to the drug.
Polymers with high solubilization capacity are capable of accepting a high drug load. Chemical features of these materials include lipophilicity, hydrogen-bonding capability, and the presence of amide groups. Amides are particularly suited to solubilizing lipophilic, poorly-soluble APIs and superior in this regard to hydroxyl-containing materials.8 Plasticizers improve processability by lowering the polymer’s Tg and melt viscosity, thus facilitating extrusion; solubilization agents prevent the API from crystallizing within the polymer.
ADVANTAGES OF HME
Solubility enhancement and sustained release are the two main justifications for embarking on an HME development project. Candidate APIs normally are BCS Class II compounds possessing high permeability but low aqueous solubility, or BCS Class IV compounds with low permeability and low aqueous solubility. For these molecules, solvation rate limits bioavailability as oral dosage forms, the preferred route of administration.
The Noyes-Whitney equation, which defines dissolution rate, states that solubility is proportional to the drug’s diffusion coefficient, saturation solubility, and exposed surface area, and inversely proportional to the diffusion layer thickness at the solid-liquid interface. HME addresses these critical factors by:
“¢ increasing effective surface area by effective dispersion or solid solution;
“¢ decreasing effective diffusion layer thickness by improving wettability (eg, through surfactants); and
“¢ improving inherent solubility by employing amorphous API forms.
HME’s ability to disperse APIs evenly throughout the matrix, at the molecular level, is arguably its leading benefit over traditional formulation like spray-drying and evaporative methods. Because HME does not use solvents, the process is safe, environmentally friendly, and requires fewer unit operations. Judicious choice of polymer matrix provides such benefits as thermal binding, chemical stabilization, solubilization, controlled release, and greater flexibility with excipients. The benefits of HME go well beyond enhancement of solubility to include:
“¢ polymeric formulation matrix, which eliminates hydrolysis associated with wet agglomeration;
“¢ suitability for sustained/controlled release or enteric coating;
“¢ applicability to capsules, tablets, bioadhesive films, multi-particulate dosage forms, and mini- matrices;
“¢ controlled dosage over a wide range of solubilities or dispersion concentrations;
“¢ film capability for buccal or patch dosage forms;
“¢ very high drug loading, up to 90%, decreases tablet size;
“¢ robust, compact, high-throughput manufacturing with little waste;
“¢ solvent-free processing, eliminating need for explosion-proof equipment; and
APIs processed as hot melt extrudates include nifedipine, indomethacin, piroxicam, chlorpheniramine maleate, 17Î² estradiol hemihydrate, lidocaine, hydrocortisone, ketoprofen, and many others. Despite these successes, HME is an under-utilized technology, particularly for development-stage compounds.
HME has an undeserved reputation for presenting undue challenges to formulation development. This is in part due to the lack of familiarity with HME, even among veteran solid dosage form experts. In addition to the processing technique itself, developers must be aware of carrier and stability issues.
Selection of an appropriate carrier is always a consideration, as the drug substance must be sufficiently soluble or miscible in the carrier. The two properties are not the same. Although in best-case situations, one would expect a fully miscible mixture to be soluble as well, solid miscibility is a poor predictor of solubility as miscible materials may phaseseparate over time. Apparent solid solubility is a much better indicator of long-term physical stability, which refers to the concentration of drug within a solid dispersion at equilibrium with crystallized drug.
Predicting the formulation’s physical stability is also sometimes difficult, particularly with respect to heat degradation and recrystallization. Processing high-melting drug substance at high temperatures is not always possible due to degradation. In these situations, converting the crystalline form of the API to an amorphous form may help. This will enable a lower extrusion temperature, and often provide a more favorable stability profile for the finished product. Another strategy involves melting the polymer before the API, thus reducing the residence time at high temperature for the drug substance.
We have found that for HME formulations, initial formation of fine aqueous dispersions is a better predictor of bioavailability than dissolution. Drug product that disperses in tests (forming a milky-white suspension of fine particles) behaves similarly in the digestive tract, and is more likely effective to release the drug in vivo.
REMOVING THE BARRIERS
To assist developers with carrier/excipient selection, and to provide a platform for testing formulation properties empirically, Catalent has developed a rapid screening capability based on developmentscale versions of its production HME system. These systems quickly generate up to several hundred grams of finished product – a suitable quantity for testing. One such system resides in Catalent’s Schondorf, Germany facility, and the other in its Somerset, New Jersey site.
The system consists of a 10-mm, 40 L/D twin-screw compounder that functions similarly to the production-scale machine. Feed rate is between 25 and 400 g/hr, with wastage as low as 3 to 5 g. Depending on the die and ancillary equipment, such as a calendaring roller device, product emerges as a sheet or rod. Adding carrier and API through separate hoppers permits varying the drug load as the run progresses. Thus, developers have the opportunity to optimize drug concentration in a single run.
Product manufactured by developmentscale HME is suitable for typical quality analysis, including thermal, microscopic, spectroscopic, and physical methods. These data are useful in developing predictive models that are applicable to manufacturing scale. For example, Catalent scientists have developed a method, based on pairing workflows with vibrational spectroscopy data, for rapidly assessing and predicting the stability of extrudates.
Solubility problems plague pharmaceutical development at every stage, and reduce the commercial potential of many pipeline drugs. Many promising molecules fail for this very reason. Approaches such as particle size reduction and emulsification to improve bioavailability go only so far in improving bioavailability. Among the various formulation strategies, HME alone has the potential to fully solubilize API within an erodible matrix and in a physical form optimal for dissolution.
Although HME evolved mostly outside of pharmaceuticals, HME’s adoption to solid dosage form development stands on solid science and engineering, and the success of numerous commercial products. Lack of experience and expertise in HME formulation has until recently stood in the way of wider adoption within the industry. Developing HME dosage forms straightforwardly and confidently has been enabled by small-scale extrusion, which has been proven to be a rapid, predictive screening tool for developing HME dosage forms. This technique, combined with low consumption of raw materials, shortens development timelines for poorly soluble drugs
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3. McKinsey & Co. interviews. June 2010.
4. Catalent/Pharmaceutical Technology Drug Delivery Landscape Survey, March 2012.
5. Karl M. Preparations of solid solutions and dispersions. In: Solubility Enhancement with BASF Copolymers. Reintjes T, ed. BASF: Lampertheim, Germany;2011.
6. Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, McGinity JW, Martin C. Pharmaceutical applications of hot-melt extrusion: part I. DDIP. 2007;33:909926.
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Dr. Hans Maier is a Head Formulation Scientist for the Modified Release Technologies business of Catalent Pharma Solutions. With more than 20 years of experience in pharmaceutical development, Dr. Maier provides technical and scientific leadership for the development of modifiedrelease technologies of solid dosage forms. His expertise includes polymer processing machinery (ie, extruders, rotational molding machines), polymer rheology, and chemical modification of polymers. He earned his undergraduate degree in Chemistry and Chemical Engineering from the University of Stuttgart/Germany and his PhD in Inorganic and Analytical Chemistry from the University of Hohenheim/Germany. Dr. Maier holds patents in engineering and design of biodegradable polymer systems.
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