Issue:November / December 2012
FORMULATION DEVELOPMENT – KinetiSol: A New Processing Paradigm for Amorphous Solid Dispersion Systems
The number of poorly water-soluble compounds in development pipelines continues to increase, and the properties of these molecules are deviating further and further from conventional drug-like characteristics. Amorphous solid dispersions are becoming widely utilized to manage solubility issues as evidenced by the increasing number of marketed drug products based on this formulation technology. Hot-melt extrusion (HME) and spray drying are the leading processing technologies for amorphous dispersion systems; however, recent trends in molecular properties have led to a subset of insoluble molecules that are difficult or impossible to process by these methods. KinetiSol, a novel fusion-based process for the production of amorphous solid dispersion systems, has recently been adapted to pharmaceutical processing, and with its unique process attributes, is providing novel solutions for difficult-to-process compounds. KinetiSol’s brief processing times, low processing temperatures, high mixing intensity, and lack of torque limitations offer unprecedented capabilities for amorphous dispersion production with thermally sensitive active pharmaceutical ingredients (APIs) and excipients, high melting point APIs, and highly viscous polymers. Moreover, KinetiSol offers the operational, environmental, and economic benefits of non-solvent processing. The attributes of the KinetiSol process, its novel applications to the field of amorphous solid dispersion processing, and its value as a commercial pharmaceutical manufacturing process are presented herein with a review of the current literature on the technology.
Since the advent of high throughput screening methodologies in drug discovery, the percentage of poorly water-soluble (PWS) drug candidates in development has continuously increased.1 Molecules emerging from discovery groups of late are continuing to deviate further from conventional drug-like properties as the boundaries of chemical space are constantly expanded in search of new and better drugs. Based on the pharmaceutical literature and the authors’ experience, the percentage of PWS drug candidates in contemporary drug development pipelines can range from 40% to 90%, depending on therapeutic area.2,3
Amorphous solid dispersion (ASD) systems have recently emerged as a leading strategy for managing the solubility-related challenges of today’s new chemical entities (NCEs). Early reviews on ASD systems pointed toward the lack of commercial products as an indicator of limited commercial viability of amorphous technologies and/or concerns with regard to the risk of physical instability. However, since this time, several products based on ASD technologies have been commercialized, including: Kaletra®, Norvir®, Prograf®, Spranox®, Zelboraf®, Intelence®, Incivek®, and Kalydeco®. The increasing number of ASD products on the market indicates industry acceptance and demonstrates the commercial viability of amorphous formulation technologies.
There are two primary approaches for producing ASD compositions: (1) fusion-based and (2) solvent-based methods.4 Although numerous technologies have been developed as derivatives of these two fundamental approaches, HME and spray drying are recognized as the leading technologies. Both processes were established commercial technologies in other industries prior to their adaptation to pharmaceutical manufacturing and are now widely applied in the pharmaceutical industry.5,6 A new technology to the field of solid dispersion processing, KinetiSol, has recently emerged in the pharmaceutical literature and has been demonstrated to produce ASD systems with the most challenging compounds and compositions. Like HME and spray drying, the basis of KinetiSol was established in another industry, commercial plastics processing, prior to its adaptation for pharmaceutical manufacturing. The viability of the KinetiSol process for production of pharmaceutical ASD systems was first established at a commercial scale and then subsequently scaled down to accommodate pharmaceutical laboratory environments and to minimize API consumption during formulations development.7 A lab-scale KinetiSol compounder, suitable for GMP use, is pictured in Figure 1.
KinetiSol is a fusion-based process that utilizes frictional and shear energies to rapidly transition drugpolymer blends into a molten state. Simultaneous to the molten transition, KinetiSol rapidly and thoroughly mixes the active ingredient with its excipient carrier(s) on a molecular level to achieve a single-phase ASD system. The real-time temperature of the composition within the KinetiSol chamber is monitored by a computer-control module, and upon reaching the user defined endpoint, molten material is immediately ejected from the process. Total processing times are generally less than 20 seconds, and elevated temperatures are observed for typically less than 5 seconds before discharge and cooling. On a lab-scale, the process is designed to operate in batch mode, whereas in commercial processing, it is operated semi-continuously, achieving product throughput as high as 1,000 kg/hr.
With its unique attributes, the KinetiSol process is providing novel solutions to emerging problems associated with ASD processing. KinetiSol’s very brief processing times enable production of ASD systems with thermally sensitive APIs and excipients. The high rates of shear inherent to KinetiSol accelerate solubilization kinetics of drug compounds in molten polymers, which typically results in processing temperatures that are well below the melting point of the API. Consequently, the production of ASD systems with high melting point compounds (>200Â°C) in a broad spectrum of concentrationenhancing polymers is routinely achieved with KinetiSol. The KinetiSol process is not torque limited, and hence processing of highly viscous/non-thermoplastic/high molecular weight polymers can be easily accomplished without the use of plasticizers. The capabilities of KinetiSol enable the use of unique drug/excipient combinations to create solubility-enhanced compositions that cannot be reproduced or manufactured at large scales by other technologies.
As established technologies in pharmaceutical manufacturing, HME and spray drying are the primary options for most PWS compounds. For molecules with acceptable thermal properties, HME is typically the technology of choice. When thermal properties are an issue, yet solubility in a volatile organic solvent is acceptable, spray drying is often the selected approach. Challenges for technology selection exist when compounds possess unacceptable thermal properties for HME and poor solubility in suitable organic solvents. It is in this area where KinetiSol provides considerable value. As a non-solvent process that can rapidly solubilize high melting point APIs in molten polymers, KinetiSol is able to satisfy unmet needs in this area of the PWS compound space. KinetiSol also supplements HME and spray drying in other areas when molecules are thermally labile or unstable in organic solution, for example. Additionally, KinetiSol may be an alternative to spray drying when cost of goods or the availability of high volume manufacturing capacity is an issue. The schematic shown in Figure 2 illustrates the rationale for process selection between HME, spray drying, and KinetiSol based on API melting point and solubility in volatile organic solvents. KinetiSol shown in a smaller font represents instances when the primary technology cannot be utilized for reasons such as those mentioned earlier.
With the increasing challenges of PWS drugs, unmet needs are emerging that cannot be satisfied with only HME and spray drying. KinetiSol offers unique and viable solutions to these issues and consequently adds substantial value to the field of ASD technologies. This article presents the unique attributes of the KinetiSol process and its novel applications to the production of ASD systems by reviewing the current literature on the technology.
KINETISOL PROCESSING OF HIGH MELTING POINT DRUGS
PWS drugs with very high melting points (>200Â°C) are emerging from drug discovery with greater frequency in recent years. High melting point compounds present significant challenges to thermal processing for the production of ASD systems, namely carrier degradation and amorphous drug-loading limitations. When processing these compounds by HME, extrusion temperatures are limited by the onset of thermal degradation of the polymer carrier, and thus processing temperatures can be 100Â°C or more below the melting point of the drug. In this processing regime, the drug must be solubilized by the molten polymer in order to achieve an amorphous composition. Solubilization of the API in the molten polymer is controlled by dissolution kinetics, and typically, the time required to solubilize the drug fraction is proportional to its melting point. This requires the use of a carrier that is capable of fully and rapidly solubilizing the API at temperatures well below its melting point, which limits the range of excipients available for formulation design. For very high melting point compounds, it can be extremely difficult or impossible to achieve target drug loads without extended residence time distributions, greater mechanical energy input, and/or high temperatures, all of which can lead to degradation of the API and/or polymer carrier.
The advantage of KinetiSol for thermal processing of high melting point compounds is two-fold: (1) the energy input typically renders crystalline compounds amorphous well below their melting points and (2) the process’s high shear rates significantly accelerate solubilization kinetics of APIs in molten polymers. Consequently, KinetiSol can render high melting point APIs amorphous at temperatures well within the thermal limits of most pharmaceutical polymers. Additionally, the rapid solubilization kinetics provided by KinetiSol allow for the achievement of high amorphous drug loadings. In this section, case studies are reviewed, illustrating the applicability of KinetiSol to the production of ASD systems with high melting point compounds.
DS901 is an experimental oncology compound that has demonstrated compelling efficacy in aggressive cancer models. The solubility of the compound in aqueous media is less than 2 Î¼g/mL across the physiologically relevant pH range. The melting point of DS901 is 295Â°C as determined by DSC, and efforts to solubilize this molecule at target amorphous drug loadings using HME were unsuccessful. Although the compound exhibits a high LogP value (8.1), its apparent caco-2 permeability (Papp) was determined to be less than 1 x 10-6 cm/s, suggesting that DS901 is a BCS IV compound.
KinetiSol processing was successfully applied to produce ASD compositions of DS901 with four different polymeric carrier systems: HPMCAS-LF, HPMCAS-MF, Eudragit® L100-55, and Soluplus® in combination with Eudragit® L100-55; each also containing a surfactant. The KinetiSol process temperature profiles for each composition are shown in Figure 3. It can be seen that all compositions were rendered amorphous at peak temperatures as much as 160Â°C below the melting point of the drug. Also, processing times at elevated temperature were less than 5 seconds for all compositions, demonstrating the rapid solubilization kinetics achieved with KinetiSol. Potency analysis revealed that the DS901 content in all formulations was in excess of 99%.
Non-sink, gastric transfer dissolution testing revealed vast improvements in the dissolution properties of DS901 for all KinetiSol compositions over the pure compound; however, the HPMCAS-LF-based formulation was determined to be superior with respect to extent of DS901 supersaturation (Figure 4A). Pharmacokinetic studies in male Sprague-Dawley rats were conducted to compare the oral absorption of DS901 from the best KinetiSol compositions versus the micronized crystalline drug. As seen in Figure 4B, all KinetiSol compositions generated substantial improvements in systemic concentrations of DS901 over the pure drug.
The results of KinetiSol processing with DS901 illustrate the capability of the process to achieve target amorphous drug loadings of very high melting point compounds in various solubility-enhancing polymeric carriers. The resulting KinetiSol formulations generated substantial supersaturation of DS901 in simulated intestinal fluids and significantly enhanced the oral bioavailability of DS901. These results demonstrated the enablement of a potential new cancer therapy by the application of the KinetiSol technology.
Meloxicam (MLX) is another example of a very high melting point compound with poor aqueous solubility that presents significant challenges for thermal processing. MLX is a non-steroidal, anti-inflammatory drug. Upon melting at 270Â°C, MLX rapidly decomposes. The compound is classified as a BCS II with solubility values in hydrochloric acid and purified water of 0.9 Î¼g/mL and 12 Î¼g/mL, respectively.
In a recent study, Hughey and co-workers evaluated thermal processing of MLX to achieve solubility enhanced formulation systems.8 The goals of these experiments were to identify polymeric carriers that enabled production of chemically stable, single-phase ASDs of MLX. Polymer screening studies demonstrated that MLX was more soluble in the Soluplus than povidone and copovidone. TGA with the physical blends (1:3, MLX:polymeric carrier) demonstrated that MLX decomposition occurred at approximately 40Â°C below its melting point without mixing, indicating that fusion processing would be problematic (Figure 5). The preparation of amorphous dispersion systems of MLX in Soluplus by HME required processing temperatures of 175ÂºC and yielded only 88% potency. With KinetiSol, processing temperatures were limited to 110ÂºC, and residence times were reduced to seconds, effectively limiting impurity formation and yielding a product potency of 98%.
The dissolution performance of the amorphous MLX:Soluplus KinetiSol composition was evaluated against a commercial MLX tablet and pure MLX by non-sink dissolution testing in 0.1 N HCl and deionized water. As seen from the dissolution profiles in Figure 6, a significant increase of dissolution rate was achieved with the KinetiSol solid dispersion versus the MLX tablet and pure MLX in both 0.1 N HCl and deionized water. These results thus demonstrated the potential of KinetiSol to enhance both the rate and extent of dissolution with a high melting point, thermally unstable, PWS compound.
KINETISOL PROCESSING OF THERMALLY LABILE DRUGS
Many PWS compounds in today’s development pipelines exhibit thermal degradation characteristics in addition to other properties that limit thermal processing, ie, high melting points. Thermal degradation of a material is most typically the result of cumulative heat exposure, which is a function of temperature and time. Therefore, the use of HME for the production of ASDs can be limited for thermally labile compounds owing to tailing residence time distributions that can expose processed materials to elevated temperatures for several minutes.
Conversely, KinetiSol processing limits exposure to elevated temperatures to just a few seconds. Moreover, peak process temperatures are often reduced compared to HME because high shear mixing allows for improved compound solubilization at lower temperatures. Therefore, KinetiSol offers significant advantages to the processing of thermally labile compounds as it reduces cumulative heat exposure through shorter processing times and lower processing temperatures.
One such example of an insoluble NCE exhibiting thermal instability is ROA, which is both acid and heat labile and decomposes at its melting point of 230Â°C.9 The compound is BCS II and has a solubility in simulated gastric fluid of 3 Î¼g/mL and a solubility in FaSSIF of 7 Î¼g/mL. Eudragit L100-55 and HPMCAS-LF were the two polymers selected to prepare molecular dispersions of ROA by KinetiSol. TGA studies revealed that ROA degraded at a faster rate at elevated temperatures when in the presence of the enteric polymers (Figure 7). This is presumably due to the instability of ROA in acidic environments and the abundance of acidic functional groups on the Eudragit L100-55 and HPMCAS-LF polymers. Faster rates of degradation in the presence of Eudragit L100-55 were also ascribed to the greater concentration of free carboxyl groups and lower pH in aqueous dispersion versus HPMCAS-LF. The acceleration of thermal degradation in the presence of the anionic polymers presented even greater challenges to the thermal processing of ROA.
The KinetiSol processing times at elevated temperature for the ROA-Eudragit L100-55 and ROA-HPMCAS-LF were limited to a few seconds and both ejection temperatures were less than 120Â°C, demonstrating processing temperatures far below the ROA melting point. When processed by HME, residence times were on the order of minutes and processing temperatures of 140Â°C and 170Â°C were required to render ROA substantially amorphous in the Eudragit L100- 55 and HPMCAS-LF compositions, respectively.
Potency analysis of the amorphous dispersion systems revealed that drug recovery was substantially higher with KinetiSol versus HME for comparable process feeds. In the case of Eudragit L100-55, the mean ROA recovery value was 70.9% for KinetiSol and 22.7% for HME. The mean drug recovery value for the HPMCAS-LF composition was 99.4% with KinetiSol and 70.9% for HME. A comparative summary of processing parameters and chemical analysis of the KinetiSol and HME products is provided in Table 1.
Non-sink dissolution testing of all compositions demonstrated rapid supersaturation after acid-to-neutral pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 hours. The results of the study demonstrated that KinetiSol was an effective method of producing solubilityenhanced ASD compositions where HME was not feasible owing to the compound’s high melting point and thermal instability.
DiNunzio et al investigated thermal processing of hydrocortisone (HCT), a heatlabile steroid, with two polymer carriers, HPMC E3 and PVPVA 64, by HME and KinetiSol.10 HME manufacturing of the HCTHPMC E3 composition could not be conducted at process temperatures below 180Â°C, and compositions produced at 180Â°C were determined to be only 75% of theoretical potency. The major impurity peak resulting from processing was determined to be the result of oxidative decomposition.
When processed by KinetiSol at 180Â°C, the HCT-HPMC E3 solid dispersion was found to yield an assay value of 83%. A further potency improvement could be obtained with KinetiSol, where HCT-HPMC E3 compositions were able to be processed to a 160Â°C endpoint to achieve an amorphous dispersion at 91.9% of target potency. Due to its unique characteristics, KinetiSol enabled processing at lower temperatures and for shorter durations, which reduced degradation of HCT.
For the HCT-PVPVA 64 composition, HME processing was possible at 160Â°C, owing to the reduced viscosity of the polymer. The extrudate product at this processing temperature was determined to be 97.4% of the theoretical drug content. Similarly, the HCTPVPVA 64 composition when processed by KinetiSol at an ejection temperature of 160Â°C was found to yield an assay value of 98.3%. Improved product potency with the PVPVA 64 carrier over the HPMC E3 carrier was attributed to improved chemical compatibility with HCT. The abundance of hydroxyl groups on the HPMC carrier was theorized to have contributed to oxidation of the compound. Subsequent HME trials with the PVPVA 64 carrier at elevated temperatures and extended residence time revealed that product potency was inversely related to process temperature and time. This evaluation of thermal processing of HCT compositions revealed that thermal exposure was minimized via lower temperatures and reduced residence times, and thus KinetiSol provided improved product potencies versus HME.
KINETISOL PROCESSING OF THERMALLY SENSITIVE, HIGHLY VISCOUS POLYMER SYSTEMS WITHOUT PLASTICIZERS
Many of the polymers commonly used in solid dispersion systems present challenges for fusion-based processing with respect to thermal sensitivity, high viscosity, or both. Often, plasticizers and other processing aids are required to reduce polymer glass transition temperatures to enable thermal processing of viscous systems or to facilitate thermal processing at lower temperatures. Because KinetiSol is not torque-limited, highly viscous polymer systems are no issue to process without plasticizers. Furthermore, KinetiSol’s very brief processing times at elevated temperature (typically less than 5 seconds) reduce thermal stress on the polymer, and hence reduction of process temperatures by incorporating a plasticizer is not required. Even further, the unique modes of shear induced by KinetiSol facilitate amorphous composition formation well below the melting point of most drugs, thus processing temperatures are typically lower with KinetiSol than HME. The elimination of plasticizers leads to increased composite glass transition temperatures and improved physical stability, in most cases.
DiNunzio et al evaluated this aspect of KinetiSol versus HME in the production of ASD systems with ITZ and Eudragit L100-55 as a lone carrier and in conjunction with Carbopol 974P.11 Eudragit L100-55 is an anionic polymer with an onset of dissolution at pH 5.5 that has been shown to provide extensive enhancement of oral absorption of PWS drugs by targeting supersaturation to the proximal small intestine.12 However, Eudragit L100-55 is a heat labile polymer, which undergoes thermal degradation at approximately 155Â°C by decomposition of carboxylic acid side chains followed by chain decomposition above 180Â°C.13 Its thermal sensitivity coupled with high molten viscosity make Eudragit L100-55 a particularly challenging polymer to process thermally, and hence plasticizers are almost always required when processing by HME. This was the case in the study by DiNunzio et al where Eudragit L100-55-based compositions prepared by HME required the aid of a plasticizer to achieve the necessary viscoelastic characteristics to enable processing. However, enablement of processing was achieved to the detriment of molecular immobility as these materials exhibited a reduced compositional glass transition temperature of 54Â°C.
Conversely, KinetiSol processing allowed for the production of ASDs without the aid of a plasticizer, resulting in an amorphous ITZEudragit L100-55 (1:2) composition with a measured glass transition temperature of 101Â°C. Examination of side group functionality of KinetiSol processed L100-55 compositions showed similar functional levels to that of the unprocessed polymer, indicating that the polymer was not degraded during processing despite being processed above its degradation onset temperature. This result is attributed to KinetiSol’s brief processing times that limit exposure to elevated temperatures to just a few seconds.
This difference in composite glass transition temperatures between plasticized HME compositions and non-plasticized KinetiSol compositions was found to directly correlate with physical stability as shown in Figure 8. ITZ crystallization was identified with the plasticized HME composition after just 1 month storage at 40Â°C/75% RH; whereas, the non-plasticized KinetiSol composition remained stable for the entire 6- month study duration.
In this study, DiNunzio et al also investigated the incorporation of Carbopol 974P into the ITZ-Eudragit L100-55 system. These researchers determined that KinetiSol was able to produce a single-phase system with ITZ, Eudragit L100-55, and the cross-linked Carbopol 974P without the use of a plasticizer. This same composition when processed by HME required a plasticizer and was determined to be two-phase with respect to the polymer carriers. This example illustrates the unique capability of KinetiSol to make compatible liner and cross-linked polymer systems to form a single-phase polymeric composite. This ability of KinetiSol to process highly viscous, cross-linked polymers is an attribute that allows it to stand out in the field of plastics processing. The ability to combine linear and cross-linked polymers creates new possibilities for the incorporation of crosslinked excipients, eg, carbomer and crospovidone, into solid dispersion systems.
Although DiNunzio et al demonstrated enhanced dissolution performance with the presence of TEC in both the HME and KinetiSol compositions, this was attributed to pore formation caused by leaching of the water-miscible plasticizer in the acidic phase of the dissolution test. Such pore formation could be achieved with a number of water-soluble excipients; eg, surfactants, low MW polymers; and is not specific to TEC. Moreover, nonplasticizing excipients would not negatively impact the composite glass transition temperature and consequently the physical stability of the amorphous dispersion.
This study thus established the unique ability of KinetiSol to process thermally sensitive, highly viscous polymers without use of a plasticizer and the corresponding improvement in physical stability of the resulting amorphous dispersion. It also demonstrated the ability of KinetiSol to homogenously process a highly viscous, crosslinked polymer into an amorphous dispersion without use of a plasticizer and perhaps presented new possibilities for the use of crosslinked materials for solubility-enhancement applications.
Dr. Dave A. Miller is the Vice President of Research and Development at DisperSol Technologies. He earned his BS in Chemical Engineering and his PhD in Pharmaceutics from the University of Texas at Austin. Prior to joining DisperSol, Dr. Miller held the position of Senior Principal Scientist at Hoffmann-La Roche, Inc. Dr. Miller has published numerous research articles, book chapters, and patent applications in the field of solubility enhancement and is co-editor of the recently published book, Formulating Poorly Water Soluble Drugs.
Dr. James C. DiNunzio currently serves as a Principal Scientist in the Pharmaceutical & Analytical R&D Department at Hoffmann-La Roche, Inc. Dr. DiNunzio earned his PhD in Pharmacy from The University of Texas at Austin, specializing in the formulation and processing of amorphous solid dispersions. He also earned his MS in Chemical Engineering from Columbia University and BS in Chemical Engineering from SUNY Buffalo. Prior to joining Roche, he served as a Senior Formulation Scientist at PharmaForm, LLC and Scientist at Forest Laboratories. He has authored numerous publications and has presented his research at national and international conferences.
Dr. Justin R. Hughey serves as the Director of Research for Enavail, LLC. He earned a BS in Chemical Engineering from The University of Texas at Austin, a BS in Chemistry from Texas State University, and his PhD in Pharmaceutics from The University of Texas at Austin. While earning his PhD, he interned in the Solid Oral Dosage Form group at Bend Research Inc. in Bend, OR. His research interests are focused on novel formulation and processing techniques to enhance the solubility of thermally labile and high melting point drug substances exhibiting poor aqueous solubility; applications of hot-melt extrusion technology for immediate release, controlled release, and solubility enhancement applications; particle engineering technologies for oral, pulmonary, nasal, and buccal delivery, controlled, and immediate release tablets; as well as analytical method development. Dr. Hughey has published and presented over 20 articles and abstracts, authored three book chapters and is co-inventor on seven patent applications.
Dr. Robert (Bill) O. Williams, III is the Johnson & Johnson Centennial Professor and Division Head of Pharmaceutics at the College of Pharmacy, University of Texas at Austin. He earned a BS in Biology from Texas A&M University, a BS in Pharmacy from the University of Texas at Austin, and his PhD in Pharmaceutics in 1986 from the University of Texas at Austin. Dr. Williams worked 9 years in the pharmaceutical industry in the US and France before returning to the University of Texas at Austin. He was elected a Fellow of the AAPS in 2006 and a Fellow of the American Institute of Medical and Biological Engineering in 2008. His research interests include development of novel drug delivery systems for oral, pulmonary, nasal, injectable, buccal, and topical applications; development of novel particle engineering technologies for low molecular weight drugs, peptides, and proteins; and analytical technologies to characterize actives, excipients, and polymers. He has published over 250 articles, abstracts, and book chapters in the fields of pharmaceutical technology and drug delivery. He is an inventor on several patents and patent applications and is the Editor-in- Chief of the research journal Drug Development and Industrial Pharmacy.
Dr. James W. McGinity is Professor of Pharmaceutics in the College of Pharmacy, The University of Texas at Austin. He earned his BS in Pharmacy at the University of Queensland, Australia, and his PhD in Pharmaceutics from the University of Iowa. Dr. McGinity’s research interests and publications are focused on solid dosage forms, aqueous film coating of pellets and tablets, powder technology, thermal processes including hot-melt extrusion and KinetiSol processing, materials science, transdermal systems, and controlled and targeted drug delivery systems. Dr. McGinity is an AAPS Fellow, is an author or co-author on over 180 scientific publications, has been issued 23 US patents, and is a Charter Member of Drug Development & Delivery’s Editorial Advisory Board.
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