Solid dispersions represent a promising formulation approach for overcoming today's major challenge in pharmaceutical formulation development: poorly soluble and poorly permeable active pharmaceutical ingredients (APIs). Solid dispersions can be obtained using different processes; however, hot-melt extrusion (HME) is extremely suitable for this purpose. One major advantage is the fact that no solvents are required; this avoids residual amounts of solvent and the accompanying stability risks during the shelf life of the formulation (see Figure 1). 

A solid dispersion is defined as a "formulation of poorly soluble compounds as solid dispersions might lead to particle size reduction, improved wetting, reduced agglomeration, changes in the physical state of the drug and possibly dispersion on a molecular level, according to the physical state of the solid dispersion. This will depend on the physicochemical properties of the carrier and the drug, the drug-carrier interactions and the preparation method" (1). 

 Figure 1: Hot-melt extrusion is an efficient processing method for obtaining solid dispersions. 			

This definition points to some of the success factors of a solid dispersion. The miscibility between the API and the carrier, often an amorphous polymer, has to be defined. The polymer has to act as a solvent for the API to immobilize it within a molecular dispersion. This can be achieved by a high glass transition temperature (i.e., high viscosity and low cold flow) but this usually leads to a kinetically stabilized system only.  

Any disturbing factor such as a slightly increased temperature or moisture can enhance flexibility in the solid dispersion and can accelerate migration of the drug; this in turn leads to nuclei formation and possible re-crystallization of the previously amorphous drug. A better solution is to utilize interactions such as hydrogen bonding between the API and the polymer to immobilize and stabilize the API in its molecular dispersion. Such systems are thermodynamically stable and are called solid glassy solutions.  

In addition to a solid glassy solution, the API can be amorphously suspended in small clusters in the carrier, which can be kinetically stabilized. This is called an amorphous glass suspension (see Figure 2). If the API is a crystalline suspension in the amorphous carrier, the system is called a crystalline glass suspension. Such systems appear stable because the crystalline state is the energetically favored state. Solid glassy solutions and amorphous glass suspensions enhance the dissolution rate of the API by providing it in a non-crystalline form. In this way energy is applied to the API to bring it to a higher energy state where the crystal lattice energy is overcome. Figure 3 illustrates this fact. Because the API is in a higher energy state when amorphous, it tends to re-crystallize. 

Figure 2: Solid dispersions based on amorphous polymeric carriers.			

Figure 4 shows the relevant parameters that determine the stability of a solid dispersion. It also describes the second challenge faced when formulating a solid dispersion: stabilization of the released API by avoiding a re-crystallization in the gastro-intestinal tract. Soluplus® was developed as a polymeric amorphous carrier to stabilize the API when molecularly dispersed in the Soluplus® matrix by its lipophilic structural elements. 

Figure 3: Energy brings the API from the crystalline to the amorphous state and to separate single molecules.			

However, Soluplus® was also developed as a polymeric emulsifier to keep the API in a dissolved state after its release into the gastro-intestinal fluids. If this were not the case, the API would likely precipitate out from its supersaturated state. In some cases, precipitation cannot be fully avoided, but Soluplus® and other polymers such as Kollidon® VA 64 can sufficiently slow down the precipitation process, thus allowing sufficient absorption of the API into the blood stream. This approach, when the API is released fast into supersaturation and starts to precipitate out, is known as the "jump-and-parachute" effect. The important parameter is the precipitation rate after supersaturation is reached. 

Figure 4: Main parameters that determine the success of solid dispersions (solid glassy solutions).			

Hot-melt extrusion is a recognized process for the manufacture of solid dispersions and innovative new dosage forms. It is an established process that has been used in the plastics and food industries since the 1930s. In the 1980s, BASF SE was the first to apply the melt extrusion process based on polymers with high glass transition temperatures (such as polyvinylpyrrolidones) to pharmaceuticals (2). 

Extruders for pharmaceutical use have been designed and adapted for mixing drugs with carriers in various dosage forms. The significant difference between extruders for thermoplastics and pharmaceutical applications is the equipment used, and hence, the contact surface, which must meet regulatory requirements. The contact parts of the extruders used in pharmaceuticals must not be reactive nor may they release components into the product. The extruder equipment is specially configured to fulfill all cleaning and validation standards applicable to the pharmaceutical industry.  

The use of extruders in the pharmaceutical industry cannot be seen as a niche application. Figure 5 demonstrates four fields of versatility of the technology. Not all the benefits available, however, have been realized to date. 

Figure 5: The four fields of versatility of hot-melt extrusion technology in the pharmaceutical industry.			

In principle, an extruder consists of barrels enclosing single or twin screws that transport and, subsequently, force the melt through a die, giving it a particular shape. The barrel can be heated to the desired temperature. Due to the external heat and shear provided by the screws, the polymer is plasticized and its viscosity reduced. Hot-melt extrusion is a typical continuous process, because the extruder is fed at one side and the extruded material exits from the other side. This makes it even more attractive for pharmaceuticals (3). The hot-melt extrusion process comprises the steps melting, mixing and shaping. 

Advantages of hot-melt extrusion in detail

Within the pharmaceutical industry, hot-melt extrusion has been used for various purposes, such as: 					

Enhancing the dissolution rate and bioavailability of a drug

Parenteral depots and topical delivery systems.

Once developed, hot-melt extrusion is a reliable and robust process offering benefits in cost-efficiency. Compared to other processes for the production of solid solutions, it is far less complex, because the manufacturing of such dosage forms requires only a few steps and avoids the use of organic solvents (Figure 6). 

Figure 6:  From poor API solubility to a final formulation.			

				Hot-melt extrusion also has advantages over solvent-based methods of forming solid solution and dispersions (Figure 7):									

Non-dusty pellets (e.g., for highly active ingredients formulations)

Figure 7: Opportunities and advantages of hot-melt extrusion. 										

To develop the melt extrusion process in an appropriate manner it is important to have tools to characterize and analyze the process. It is clear that only an optimized formulation together with an optimized process set-up will yield the best product. 

Besides the parameters such as screw speed and feed rate, which can be adjusted during the extrusion process, screw configuration is a major parameter. Screw design is not often optimized although it plays a major role in determining product quality. Screw configuration basically determines the shear stress. It also strongly influences the residence time distribution. BASF's second edition of the HME compendium provides more information on the design of screws in co-rotating twin screw extruders. Here, the functionality of different screw segments is explained in detail. 

The new HME compendium also shows how to determine residence time distribution and how to read it. It provides a guide for process analysis and for developing better process understanding. 

BASF has also developed a process parameter chart that enables the whole extrusion process with all its influencing variables to be included. The advantages of the new process parameter chart are: 					

It also displays the economic effects of changes made in process design. 

It is scale-independent and can be used in scale-up procedures.

The proposed process parameter chart is shown in Figure 8. It is a XY-diagram, displaying the volume-specific feed load (VSFL) versus the extrusion temperature (mean barrel temperature). 

Throughput triggers cost. The throughput in an extruder can be either torque-limited or volume-limited. In Figure 8, one curve represents the determined maximum achievable VSFL values at the limit of the extruder. The vertical line indicates the process boundary. Only the position on the temperature axis is relevant for reading the line; the line height does not matter. Each VSFL value to the left of the line is limited by the maximum torque of the extruder (configuration), while each VSFL value to the right of the line is limited by maximum intake (volume). The vertical dotted line on the right indicates the process boundary given by the maximum allowable temperature, which can be determined by the degradation points of either the active substance or any non-active ingredient in the processed formulation. The design space can be filled with contour lines of extrusion system parameters such as mean residence time for better process analysis. 

More information on the process parameter chart and its use can be found in BASF's new HME compendium (see below). 

Articles

The advantages and disadvantages of hot-melt extrusion in solid dispersion formulations.

Solid Dispersions by Hot-Melt Extrusion

Spray drying is a key process for manufacturing amorphous dispersions because of its breadth of applicability. The wide range of potential atomization techniques and controllable drying kinetics enables amorphous spray-dried dispersions (SDDs) to be produced from a wide variety of active pharmaceutical ingredients (APIs). Moreover, spray drying is a continuous, efficient, and well-characterized process that can be easily scaled up from development to pilot to production scale. The use of spray drying for pharmaceutical applications is important because amorphous dispersions are key delivery technologies for increasing the solubility of BCS Class II and IV drugs, which represent more than 50% of the compounds in pharmaceutical company pipelines. 

Bend Research, a leader in the production of amorphous dispersions for pharmaceutical applications, has devoted a substantial amount of work to the application of fundamental engineering principles to the spray drying of amorphous dispersions. Application of fundamental knowledge has made it possible to obtain spray-dried amorphous dispersions with the desired stability and performance attributes, smooth process scale-up, and downstream manufacturability.  An overview of the process and product is shown in Figure 1. 

 Figure 1: Spray drying process and key amorphous dispersion attributes.			

The spray drying process is amenable to the manufacture of amorphous dispersions across a wide range of API physicochemical properties. Mechanistic understanding of the dissolution mechanism is critical during formulation selection. Dissolution of the primary solid dispersion particle to free drug or high-activity drug species is necessary to enchance the bioavailability of the amorphous solid. 

To increase the efficiency and robustness of formulation selection, "guidance maps" are used that account for key API properties related to physical stability and performance. Drug loading and polymer selection can be efficiently optimized to achieve the desired performance attributes of the dispersion (1). The process space is then selected to provide a robust manufacturing window.  			

Physical stability during spray drying is maintained through the rapid drying kinetics of high-surface-area droplets. Rapid quenching of droplets to achieve a low mobility state, facilitated by use of a high-T

 polymer, is critical to achieving an amorphous dispersion.  Atomization and drying conditions are both optimized to ensure a reproducible, robust process that achieves a molecular dispersion and promotes physical stability during in-process hold times. 

The spray drying process is broadly applicable to a large number of APIs and formulation approaches. Multiple spray solvents can be successfully used, simplifying the formulation of many drug and polymer combinations.  

Figure 2: Overview of droplet-to-particle history. 			

Fundamental understanding of the spray drying process requires definition of a control volume to identify the key physical situation. Mapping the process from droplet formation to particle formation, as shown in Figure 2, is critical to accurate prediction of the impact of process variables on final particle attributes. By matching the conditions encountered during the droplet-to-particle history, the critical-to-quality product attributes can be achieved, independent of process scale. 

Figure 3: Process development flowchart. 			

A rational flowchart methodology based on this fundamental knowledge can be applied to optimize the spray drying process, focusing on two core processes: atomization and drying (see Figure 3) (2). 			

Numerous atomization techniques can be employed to manufacture specific particles sizes for applications such as oral solubilization (10 to 100 µm) and engineered particles for inhalation (1 to 5 µm).  Engineering correlations are combined with an experimental approach. Experiments are conducted to select target droplet-size distributions through changes in atomizer geometry and operating conditions to achieve the target operating ranges and final particle size. 

Drying conditions are selected based on physical-stability constraints and the desired morphology or density of particles. Process parameters are correlated to particle attributes, serving as a basis for scale-up. 

Use of engineering fundamentals in the spray drying process for amorphous dispersions allows understanding of key process parameters and their impact on performance, manufacture, and stability.  The process is easily scaled and is applicable to with a wide variety of APIs. 

Spray drying is a key process for manufacturing amorphous dispersions because of its breadth of applicability. The wide range of potential atomization techniques and controllable drying kinetics enables amorphous spray-dried dispersions (SDDs) to be produced from a wide variety of active pharmaceutical ingredients (APIs).

Spray Drying of Amorphous Dispersions

Solubilizers play an important role in dissolving poorly soluble molecules. As the number of poorly soluble lipophilic and/or hydrophobic molecules increases—whether as "brick dusts" or waxy substances—the industry is struggling to identify the appropriate lipophilic excipients (surfactants, solubilizers, solvents or polymers) that can be used to develop such poorly soluble formulations into solid dosages and other forms of pharmaceutical products. Furthermore, the complexity of such formulations is increasing and often two or more solubilizers and/or cosolvents are required to develop stable and efficacious formulations with enhanced bioavailability (1). 

As pharmaceutical manufacturers develop generic and new molecules that require high-quality, functional excipients, they seek support from excipient manufacturers. Indeed, the pharmaceutical industry relies on excipient manufacturers to design and produce excipients that are appropriate to the envisaged dosage form and API. This is a complex undertaking made all the more difficult because of the number of different names that manufacturers use for their excipients. However, several excipient manufacturers are now streamlining the structure, nomenclature and functionality of their excipients, including solubilizers. 

Such rebranding has been used in other industries to reduce complexity and to promote products on the merits of their performances and qualities, ideally without undermining the old brands. This is now occurring among excipient manufacturers, particularly those that carry lipophilic excipients, including BASF, as well as other companies. Many companies have used branding and rebranding to either introduce new products or reintroduce an old product under a single 'prefix' to simplify identification. In the case of BASF, Cremophor®, Solutol®, Lutrol® and other solubilizers will become part of the Kolliphor® brand family.  

The basis for rebranding with the same prefix is to identify molecules by structures, functions and the applications of choice; enable the company's brand products to be recognized; and to differentiate pharmaceutical excipients from other grades. Rebranding is a tedious and time-consuming process, and in some instances adds complexity if the functionality of the molecule is not well defined. 

Here, we provide a synopsis of how we have undertaken the process of rebranding our solubilizers for pharmaceutical applications. With a few exceptions, we have tried to preserve some of the characters from the old product brand name to avoid confusion and to allow scientists to easily recognize them. The surfactants and solubilizers, as well as related products, have been categorized under four umbrella rebranding subgroups: 					

 For amphiphilic substances such as ionic and non-ionic surfactants, solubilizers and emulsifying agents, as shown in Table I.

 For solvents such as mediumchain triglycerides, propylene glycol, liquid polyethylene glycols and liquid poloxamers, as shown in Table II.

 This name was coined to represent consistency factors, such as those in fatty acids, alcohols and glycerides, as shown in Table III.

 The name was chosen to represent emollients such as fatty acid esters and special fatty alcohols, as shown in Table IV. 

Rebranding gives us the opportunity to include other solubilizers and related excipients based on their chemistry and functionalities in our four umbrella subgroups. With continuing interest to increase drug solubilization, it is our understanding that this rebranding will reduce the complexity involved in selecting pharmaceuticalgrade excipients in formulation development. Thus, this will encourage excipients manufacturers to adopt a norm to simplify complex product portfolios.  

1. C.J.H. Porter, C.W. Pouton, J.F. Cuine and W.N. Charman, 

Download your free copy of BASF's solubility enhancement compendium at: 

Solubilizers play an important role in dissolving poorly soluble molecules. As the number of poorly soluble lipophilic and/or hydrophobic molecules increases-whether as "brick dusts" or waxy substances-the industry is struggling to identify the appropriate lipophilic excipients (surfactants, solubilizers, solvents or polymers) that can be used to develop such poorly soluble formulations into solid dosages and other forms of pharmaceutical products.

Rebranding Lipophilic Excipients

In drug development, the majority of new chemical entities are lipophilic and/or poorly soluble. New actives often fail during development due to these challenging properties. The solubilization of actives is therefore an important approach towards improving the bioavailability of a drug molecule in an accepted dosage form. 

In this special issue, BASF would like to open up a discussion about solubilization challenges and innovative solutions, focusing on both products and cost-effective production technologies, such as hot-melt extrusion and spray drying. Because innovation is always the result of many, companies such as Catalent, Bend Research and Johnson & Johnson have also contributed with their expertise on this topic. 

True to its legacy of innovation, BASF continues to develop new innovative solubilizers, such as Soluplus®. Thus, together with our established portfolio of Kolliphor® solubilizers and Kollisolv® cosolvents, we offer a versatile toolbox capable of coping with the many solubilization challenges facing our industry. This, in combination with our SoluHTS® screening robot, enables the industry to screen and identify the most suitable solubilization excipients faster, thereby shortening their product development time. 

In the end, there is no single way out of the "maze of pharmaceutical development." However, the use of new technologies and innovative products may get us out quicker. 

In drug development, the majority of new chemical entities are lipophilic and/or poorly soluble. New actives often fail during development due to these challenging properties.

Collaborative Work can Lead to Innovation

A Q&A with Karl Kolter, PhD, Head of Pharmaceutical Excipients R&D, BASF

 Excipients add important functionality to a formulation. With respect to solubility improvement specifically, how can excipients be used to improve solubility and therefore bioavailability? Can you provide examples in terms of the functionality and the type of excipients that may be used?  

Solubility and speed of dissolution can be influenced by various excipients. Here, I would distinguish between excipients that act directly on the active and those, such as disintegrants, that simply ensure quick disintegration of the dosage forms. The first class is represented by wetting agents, solubilizers, protective colloids, adsorbents and so forth. All of these can contribute to improved dissolution, the strongest effect coming from solubilizers. Solubilizers are typically surfactants of a relatively low molecular weight, such as Polysorbate 80, Kolliphor®  EL (formerly Cremophor®  EL) and many other ethoxylated materials. With the launch of Soluplus®  in 2009, the first polymeric solubilizer appeared on the market offering new opportunities, particularly for tablets.  

 What are the key properties of an excipient to determine whether it will be an effective solubilizing agent? What type of pharmacodynamic and pharmacokinetic data is used to evaluate solubility and bioavailability, and what is the influence of the excipient on these levels?  

The main prerequisites for a solubilizer/bioavailability enhancer are that it is capable of overcoming the crystal lattice energy of a drug and that it can be delivered into the aqueous fluids of the GI-tract. Taking into account that the ideal excipient has to act as a bridge between the high lipophilicity of the poorly soluble active and the high hydrophilicity of aqueous fluids, it should be amphiphilic. 

 dissolution studies must be accompanied by 

 studies in animals or humans to reveal whether improved dissolution really leads to enhanced bioavailability. To give you an example of what excipients can generate: a Soluplus® -itraconazole formulation resulted in 25-fold higher bioavailability than itraconazole alone and outperformed the marketed drug by a factor of 2.3. This shows the potential associated with unique excipients. 

 What type of predictive tools can be used to evaluate the optimal levels or type of excipient(s) to be used in a formulation with respect to bioavailability enhancement?  

There are screening methods available which can be used to find the best solubilizer for a particular active such as the solubilizing power in aqueous solution and the solid solution capacity. These tests, which are described in detail in the BASF booklet "Hot-Melt Extrusion Compendium" determine how much drug can be dissolved either in the aqueous or solid phase, which is mainly the polymer. From the results of these tests, a preliminary formulation can be derived which of course needs to be further optimized not only regarding performance but also processing. 

 What role can excipients play with respect to certain technologies such as hot-melt extrusion, as an approach in resolving solubility challenges? Do they facilitate the formation of the solid dispersion? Can the excipient also facilitate processing in a hot-melt extrusion process? Can you offer specific examples of either application?  

For the preparation of solid dispersions or solid solutions, two technologies have become popular so far: hot-melt extrusion and spray drying with organic solvents. These are completely different from a processing point of view and also have different requirements.  

For hot-melt extrusion, a low glass-transition temperature and low melt viscosity enable processing at lower temperatures to be carried out, thus avoiding drug degradation. Soluplus®  for instance was developed especially for hot-melt extrusion and fulfills this target profile ideally. There is no other material that runs so smoothly on an extruder and that is able to take up so much poorly soluble active. 

 Poor solubility is an obvious barrier to advancing potentially efficacious drug candidates. Looking into the future of solubilization, what key technologies are currently being employed and which are being evaluated for further development? What role will excipients play in those efforts?  

Hot-melt extrusion is currently in the stage of becoming a mature technology in pharma; however, this process can still be modified further to obtain even better results. Furthermore, new solubilizers with unique properties need to be developed so that all kinds of poorly soluble actives can be addressed. The area of nanoformulations, for example, has not been fully explored. 

However, one of the biggest hurdles facing industry is the regulatory issue of using a new excipient. There is some reluctance to use a new excipient for the first time. A Novel Excipients Consortium of pharmaceutical companies and excipient suppliers has just been created with the specific aim of paving the road for new excipients. To use the words of Martin Luther King, "I have a dream" that one day excipients will have their own approval process. This achievement would remove the risks from pharmaceutical companies and their drug approvals, speed up drug development, innovate formulations, and ultimately improve treatments. 

Addressing the Solubility Challenge

In early 2012, BASF and Catalent formed an open alliance aimed at providing solutions for bioavailability. To understand the details of the collaboration and its goals, we spoke to representatives at each company. Participating in the round table were: Martin Widmann, Senior Vice-President of Pharma Ingredients & Services at BASF and Ian Muir, PhD, President of Modified Release Technologies at Catalent. 

 Can you explain what each company is contributing to the alliance and how the collaboration functions? 

 BASF and Catalent have complementary offerings and knowledge that address the same customer needs: the enhancement of solubility and bioavailability of poorly soluble drugs. BASF has the broadest portfolio of solubilizers in the industry. 

 Together, we will build efficiencies for our customers along the value chain from formulation development and ingredient selection through manufacturing process selection to the finished dosage form—bringing more products and better treatments faster to the market. Catalent has 75 years of heritage enhancing bioavailability with our Softgel technology and has recently expanded its OptiMelt™ hot-melt extrusion capabilities in the US and its Schorndorf, Germany, facility.  

 Below left to right: Ian Muir, Catalent, and Martin Widmann, BASF.			

 The collaboration joins two companies with formulation development and manufacturing expertise. How does the collaboration go beyond a traditional supply relationship? What is meant by an open alliance?  

 "Open" means that both partners have joined forces on a nonexclusive basis, because we think that this is the most efficient approach to the market and one that maximizes the reach of both companies. The idea is to provide support in excipient selection for a particular customer need and to provide access to Catalent's formulation and manufacturing experts and leading drug delivery technologies.  

 Catalent wants to keep full flexibility in the choice of excipients for its customers, and the open alliance arrangement ensures that customers are not limited to the excipient portfolio of one supplier. The major advantage of the BASF portfolio is the access to its different chemistries, which makes matching to optimize solubility all the more likely. The open alliance will provide customers with formulation expertise across BASF and Catalent and in turn offer seamless bioavailability enhancement solutions from molecule to market.  

 The alliance was specifically formed to respond to client problems in resolving problems of bioavailability of BCS Class II and IV poorly soluble compounds. What are the potential solutions that can be used to resolve these challenges from an excipient and technology perspective? 

 Catalent is the leading industry partner in the development and formulation of drugs, biologics and consumer health products and a world leader in drug delivery technology. Bioavailability enhancement can be addressed through multiple approaches, including optimizing the API, formulation, processing technology, and/or drug delivery dosage form. Our technologies range from OptiForm™ high throughput screening to Softgel technology and OptiMelt™ hot-melt extrusion to highly differentiated controlled release tableting technologies such as OSDrC OptiDose™. 

 Our Kolliphor® range of products, including poloxamers, hydrogenated castor oil, TPGS and others offers a wide variety of properties that match the physicochemical properties of active ingredients. The latest innovation in this field is Soluplus®, which won the Silver CPhI Innovation Award in 2010.  

 Hot-melt extrusion is one potential solution for resolving bioavailability issues. Can you provide details on the companies' expertise in this area? 

 BASF is a recognized world-leading manufacturer and innovator of pharmaceutical excipients. We offer a line of polymers designed specifically to increase solubility in general and for use with hot-melt extrusion in particular. We have significant investments year on year in the development of pharmaceutical excipients because we believe that today's formulation challenges can not be solved with yesterday's excipients. Furthermore, BASF has decades of experience in the hot-melt extrusion technology in plastics as well as in pharmaceutical applications. 

 Catalent is the world-leading solubility solutions provider, with Softgel and OptiMelt™ hot-melt extrusion. Its capabilities range from development, formulation, pilot, commercial manufacturing to differentiated drug delivery on a global scale. 

 Will BASF and Catalent staff jointly work on a project for a given client?  

 Catalent will cooperate with BASF to optimize solubility from excipient selection, formulation, process technology to drug delivery and dosage form for customers desiring an integrated approach. By providing our customers with the option of working with a team of experts across our companies, we will increase efficiencies for them from development to scale-up to commercial, hence enabling them to deliver more products to market. 

 Nobody knows our products better than we do. This know-how in the application of our excipients is brought into the alliance by training and supporting the Catalent formulation experts. Where appropriate, experts of both companies will work together on customer projects to find optimal solutions. 

 What feedback have you received since the collaboration began? 

 The announcement generated a lot of interest in the market because every formulator is concerned about the solubility challenge. 

 Not only in the market, but also internally, everybody is excited about the opportunity to jointly cover the whole pharmaceutical value chain from excipients to finished drugs. 

A round table with Catalent and BASF on their new collaboration to provide bioavailability solutions.

Open Alliance

Soluplus®, a graft copolymer of PEG comprising polyvinyl acetate and polyvinyl caprolactam (see Figure 1A), was specially designed to solubilize poorly water-soluble drugs. To guarantee appropriate processability (e.g., in melt-extrusion applications), the composition of the polymer was adjusted to optimize its physical properties. With a low glass-transition temperature of around 70 °C, Soluplus® can be processed at low temperatures. Soluplus® shows good stability. Its formulations remain stable so that drugs, especially those that are formulated in an amorphous state, do not show recrystallization. In addition to these composition-related properties, the physical appearance of Soluplus® has  been optimized. Using a special drying process, Soluplus® is formulated as free-flowing granules (see Figure 1B) that allow high feed rates and dust-free handling during the feeding process. At the same time the granules can easily be blended with most API crystals without showing segregation in subsequent process steps.  

The unique chemical structure of Soluplus® enables it to interact with a large variety of chemical substances to form water-soluble complexes. Soluplus® is therefore considered suitable for increasing the bioavailability of many active pharmaceutical ingredients (APIs) that otherwise suffer from low solubility, which is a common attribute of most new chemical entities. In a previous study, it was shown that the bioavailability of fenofibrate, danazol and itraconazole was significantly increased when the drugs were formulated in a solid dispersion with Soluplus® via a melt-extrusion process (1) . 

 Figure 1: Chemical structure of SoluplusÂ® (A) and physical appearance of the product (B).

Although the above mentioned study demonstrated the enhanced bioavailability of the investigated drugs, it also compared drug formulations with Soluplus® using only the crystalline form of the API. However, the crystalline form is not an ideal benchmark for comparison, considering that it is not optimized and is not expected to show comparable biovavailability.  

Therefore, a new case study was performed by selecting the marketed formulation of a poorly-soluble drug (itraconazole) that had already been optimized with regard to the bioavailabity of the formulated API (2). 

Sempera® is a formulation of itraconazole that contains sucrose, corn starch, hypromellose and PEG 20,000 in addition to the API (3). The product was used as a benchmark and compared with a Soluplus®-based itraconazole extrudate. The melt-extruded formulation (20% itraconazole, 80% Soluplus® was prepared with a 16 mm twin-screw extruder (Polylab, Thermo-Fisher, Germany) at 160 °C, 200 rpm and a feed rate of 1000 g/h. Before the formulations were compared 

, characterization of certain properties was performed. 

Figure 2: DSC thermograms show no crystalline itraconazole for the SoluplusÂ® formulation (red). Interpretation for SemperaÂ® was impossible due to overlaid peaks. 

Differential scanning calorimetry (DSC) analysis showed the absence of any crystalline substances in the Soluplus® formulation (see Figure 2). Itraconazole in Sempera® seemed mainly amorphous, but an interpretation of the thermograms was impossible due to superimposed peaks from other excipients (PEG, sucrose). 

Dissolution studies with the two formulations in simulated gastric fluid (USP) showed comparable dissolution profiles and a strong oversaturation of the drug in the release medium in both cases (see Figure 3). 

Figure 3: Dissolution study of itraconazole formulations (USP  paddle, 700 ml SGF). In both cases, a massive oversaturation could be achieved compared to the crystalline drug. 

study, each of the formulations was given to five beagle dogs in the form of an individually filled hard gelatin capsule that contained a dose of 10 mg of itraconazole per kg of body weight. Blood samples were taken at predefined sampling times and itraconazole plasma levels were analyzed by a chromatographic method. 

Figure 4: Plasma level profiles in beagle dogs after administration of the different itraconazole formulations. The highest bioavailability was found for the SoluplusÂ® formulation.

The test formulations were tolerated well and there were no clinical findings. Both formulations, Sempera® and Soluplus® extrudates, achieved a strong increase in bioavailability, compared with crystalline itraconazole (see Figure 4). However, the results  from 

 plasma concentrations did not really correlate; the observed effect was much higher for the Soluplus®-based extrudate. The corresponding area under the curve (AUC 0-72 h ) increased more than two-fold compared to the Sempera® formulation (8.503 ng*h/mL versus 18.558 ng*h/mL). 

This case study confirms the results obtained from previous studies and demonstrates once more that it is possible to achieve a significant increase in oral bioavailability with a Soluplus® formulation. Furthermore, the tested melt-extruded formulation was very easy to formulate and performed significantly better than the more complex marketed formulation. It is the authors' opinion therefore that Soluplus® can therefore help to bring promising new chemical entities to the market and shorten development times by an easy and fast formulation process via melt extrusion. 

1. M. Linn et al., "Soluplus as an Effective Absorption Enhancer of Poorly Soluble Drugs 

2. F. Guth et al., "Bioavailability Enhancement of Itraconazole with Solid Solutions Based on Soluplus," presented at the 39th Annual Meeting and Exposition of the Controlled Release Society (CRS), Quebéc City, Canada 2012. 

Soluplus®, a graft copolymer of PEG comprising polyvinyl acetate and polyvinyl caprolactam, was specially designed to solubilize poorly water-soluble drugs.

Bioavailability Enhancement

Development of viable dosage forms for poorly water soluble compounds continues to be a significant challenge to the formulation scientists in pharmaceutical industry and insufficient bioavailability of such compounds due to poor formulation design may result in delays in development or cause them to be dropped from the pipeline (1,2). Various solubilization techniques such as using surfactants, co-solvents and cyclodextrins, adjusting the formulation pH, and screening salts have been developed, but these conventional techniques are not always effective enough to achieve the desirable solubility enhancement for an increasing amount of difficult-to-formulate compounds. Recently several new solubilization technologies have advanced significantly with commercial successes. This article only focuses on two excipient-enabling techniques: lipid-based formulations and solid dispersion approach, and discusses how excipients play a critical role in these innovative solubilization technologies. 

With several commercial successes including Sandimmune® and Neroal®(Cyclosporine A), Norvir® (Ritonavir) and Fortovase® (Saquinavir), lipid-based formulations have drawn considerable interest and attention in pharmaceutical industry as effective ways to improve oral bioavailability of poorly water soluble compounds (3,4). In principle, this approach is to dissolve the lipohilic drug in oils, emulsify the oil phase in water, and maintain the drug in the solubilized state in the gastrointestinal tract until absorption has occurred. Very often the lipid formulation is designed in such way that it tends to generate and maintain a supersaturated drug concentration in vivo for improved oral absorption (5). In some cases nanoparticulate emulsions are formed. Excipients definitely play a most critical role in the formulation performance.

One of the most critical criteria of the excipients used in lipid-based formulations is its solubilization capacity. The excipient or excipient blend must be able to fully solubilize the entire drug dose, preferably in a volume of a single oral dosage. This is often achieved by careful screening of appropriate oils, co-solvents and surfactants. 

Both long-and medium-chain triglyceride oils with different degrees of saturation have been extensively investigated for the design of lipid-based formulations. Co-solvents have been also used to help dissolve the drug or a large amount of the hydrophilic surfactant in the formulations. Examples of such co-solvents include ethanol, propylene glycol and polyethylene glycol. 

Surfactants with a relatively high hydrophilic/liphophilic balance (HLB) are often needed to provide a good dispersing/self-emulsifying performance. For example, polysorbates, Cremophor® (rebranded to Kolliphor® EL/ RH40) and Solutol® HS15 (rebranded to Kolliphor® HS15) are used as the surfactants due to their relatively low toxicity and excellent performance. 

In addition to the solubilization capacity, excipients in the lipid-based formulations must maintain the drug in the solubilized state in the gastrointestinal tract, preferably in supersaturable high concentration, until absorption has occurred. Therefore excipient type/composition and excipient/drug ratio are the critical factors. For supersaturable lipid-based formulations, the metastable supersaturated drug concentration has to be maintained for a long enough time period sufficient for adsorption before drug precipitation occurs. This is often achieved by temporary inhibition of drug precipitation using excipients as precipitation inhibitors (6). For example cellulose derivatives and vinyl polymers have been widely studied as precipitation inhibitors. Examples of such polymers include hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), hypromellose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), and vinylpyrrolidone/vinylacetate copolymers (PVPVA). The studies showed that HPMC and PVP were the effective precipitation inhibitors to prolong the supersaturable drug concentration for the significantly improved bioavailability of poorly water soluble compounds (7,8). 

Some Poloxamers also exhibit precipitation inhibitory effect in the tested compounds. Studies showed that Poloxamer 407 (rebranded to Kolliphor® P407) and Poloxamer P338 (rebranded to Kolliphor® P338)  inhibited the compound precipitation in the simulated intestinal fluid (SIF) at concentrations below their CMCs 9. Combinations of Kolliphor® P407 or Kolliphor® P338 with Vitamin E TPGS (rebranded to Kolliphor® TPGS) showed significantly stronger inhibitory effects on the tested compound than the individuals, indicating synergistic effects on inhibition of drug precipitation 10. The lead formulation comprising Kolliphor® P407 maintained the tested compound concentration at 300 μg/mL upon dilution in SIF for at least two hours compared with the compound alone at  less than1 μg/mL of its concentration, and increased oral bioavailability significantly (11). 

Despite much effort on lipid-based formulations, the success of commercial products is limited to a few active pharmaceutical ingredients. The complexity of such formulation and product development requires extra efforts. Also, the effect of excipients on the bioavailability of the lipid based formulations is highly complex; the in vivo performance of such formulations is poorly predictable. Furthermore, excipients with both acceptable toxic profile and high solubilization capacity for lipophilic drugs are limited. Very often a large amount of surfactants and co-solvents are needed in order to achieve the targeted dose level and to form stable microemulsions. Such a large quantity of excipients might raise safety concerns or compromise shelf-life stability of the products in the lipid base formulations. 

A solid dispersion is a homogeneous mixture of one or more active ingredients in an inert carrier at the solid 12. It can be classified into simple eutectic mixtures, solid solutions and glass solutions. Solid dispersion approach, in particular, formation of glass solutions of poorly soluble compounds using amorphous excipients with high glass transition temperatures (T

), has been used to increase dissolution rate and solubility of low solubility compounds for improved oral absorption. Recently several poorly water soluble drugs with solid dispersion formulation approach have been successfully launched in the market. 

The strategy of solid dispersion approach is to a) convert crystalline drug into to amorphous one, b) disperse the drug in a hydrophilic excipient carrier at molecular level. Such transformation leads to generation of amorphous glass solution, improved wetting, and reduced particle size of the components to the molecular level, which contributes to increased drug dissolution rate and solubility. To achieve this goal, selection of excipients is crucial.

First of all, excipient miscibility with the drug is important. Excipients must be miscible with the drug in such that the drug can be either molecularly dispersed or form an amorphous precipitate into its excipient matrix. A glass solution will not form if the drug and excipient are immiscible at the tested ratio. The drug/excipient miscibility can be assessed by DSC or predicated with Hansen solubility parameters in some cases. In addition to type of excipients, miscibility of the drug with excipients is dependent on the excipient/drug ratio in the formulation. 

Also, the physical stability of amorphous solid dispersion is one of the most critical considerations during excipient selection. The amorphous solid dispersion is metastable, and the drug will re-crystallize inevitably with time. In order to stabilize amorphous solid dispersion, polymer excipients with high T

, such as PVP and HPMC, have been selected so that Tg of the dosage form is well above ( more than 500C) the storage temperature (13). As a result, the amorphous drug in the solid dispersion is “immobilized” in a hard, brittle glassy matrix, which prevents or slows down drug recrystallization with time (14). In addition to miscibility and physical stability requirements, the excipients for solid dispersion must be non-toxic and pharmacologically inert, and stable during manufacturing processes. 

Various excipients have been extensively studied to the formation of glass solutions in solid dispersion approach (15). They are usually hydrophilic polymers. Examples include sugars, such as dextrose, fructose, galactose, trehalose, and sucrose, or amorphous polymers such as PVP, Polyvinylpyrrolidone- co-vinylacetate (PVPVA) and HPMC. Among them PVP, PEG, HPMC have received increasing attention, and been successfully used in commercial products including Sporanox®, Intelence®; Certican®; Nivadil®; Prograf® (HPMC), Cesamet®; Kaletra® (PVPVA) and Gris-PEG® (PEG 8000). The excipient type, molecular weight, and excipient/drug ratio can affect drug/excipient miscibility, chemical and physical stability during manufacturing process and shelf-life of the solid dispersion formulations.

Despite the huge efforts and commercial product successes, this approach is limited by the number of excipients that are able to stabilize metastable amorphous formulation for acceptable shelf-life stability. Very often a significant amount of excipients have to be added in order to achieve such physical stability of the formulation, but this might also result in unacceptable large dosage form size. In addition, even current excipients are not always effective in stabilizing the formulation for acceptable shelf-life stability, and selection of excipients is drug specific. As a result, the physical stability of amorphous solid solutions is still one of the main reasons why only a few amorphous solid solutions have made it to the market. Therefore development of new excipients that are able to achieve physical stability of the formulation is of significance to the solid dispersion approach. 

The success of novel solubilization techniques such as lipid base formulation and solid dispersion approach has been demonstrated with the launch of commercial products for improving oral bioavailability of poorly water-soluble compounds. Excipients have played an essential role in such excipient-enabling technologies. Nevertheless, the number of effective solubilization techniques is limited to the increasing amount of difficult-to-formulate compounds. In particular, it still remains a significant obstacle and challenge to formulate poorly water soluble compounds with high dose requirements even with current solubilization technologies. Future efforts may involve exploring and developing new excipients for high-dose drug formulations. For example new oils with high solubilization capacity are much needed to dissolve more lipophic drugs in a lipid based formulation approach, while a novel potent excipient for stabilizing physical stability of solid dispersion will reduce the amount of excipients to achieve high drug loading. The toxicity and regulatory consideration are the critical aspects of such new excipient development. 

In addition to the development of new excipients, it is worth exploring combining widely used excipients in formulation screening to produce a synergistic effect for an optimized product performance. Using high throughput and automation techniques, scientists can screen rapidly thousands of excipient combination in various formulations such as lipid formulation, and solid dispersion using small quantities of compounds (16), something that would be difficult to do manually. It is an efficient and cost-effective way to find new applications of currently used excipients in solubilization technologies. 

Another key aspect of excipient selection in new solubilization technologies is the structure-property correlation in the formulation. Current excipient selection is often empirical or semi-empirical. The interaction of excipients with drug in the formulation is poorly understood and development of the in vitro/in vivo correlation still remains an obstacle to the new solubilization technology based formulations. With more understanding of interactions of the drug with excipients in the formulation and the drug/excipients with the gastrointestinal tract environment, it could be possible in the future to establish structure-property correlation in the new techniques based formulations.

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Development of viable dosage forms for poorly water-soluble compounds continues to be a significant challenge for formulation scientists, and insufficient bioavailability of such compounds may result in development delays or failures.

Pharmaceutical Technology Europe-09-02-2012