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Active pharmaceutical ingredients are classified according to the Biopharmaceutical classi¬cation system into four classes based on drug solubility and gastrointestinal permeability (Table 1). This classification is widely used during the drug development process to inform the route taken to formulate a drug into a dosage form. Within the BCS, class II is de¬ned as drugs of low solubility and high permeability and is non-polar(G.L. Amidon 1995). In fact, most recent developed drugs have poor water solubilitysince they have hydrophobic property (Vasconcelos,2007); in other words, these drugs easily permeate the gastrointestinal membrane since the GI membrane has hydrophobic (lipophilic) components; in contact, these drugs lack the ability to be soluble in hydrophilic GI fluid which consequently affects the bioavailability of these drugs(Streubel,2006- Ohara 2005). Poor bioavailability is an important issue as it will influence the final product efficacy and increase its side effects; moreover, it may increase the development times and cost. Therefore, improvement of the solubility of the class II drugs is a significant challenge to pharmaceutical industry. Recently, different approaches have been tried to increase the solubility of class II drugs, and one of these approaches which is being intensively studied is solid dispersions.
(Table 1) Biopharmaceutical classi¬cation system of APIs:
Solid dispersions are one of the most promising techniques for improving the solubility, absorption and the efficacy of drugs. Furthermore, for clarification a comprehensive definition of solid dispersion; is the dispersion of one or more active pharmaceutical ingredients (APIs) which have poor water solubility in a carrier or matrix at solid state (e.g. polymers) which has high water solubility(Chaudhari.P.D,2006 -Dhirendra, K,2009) ; therefore, it is a solid mixture of hydrophobic drugs (APIs) and hydrophilic carrier (polymers). Furthermore, numerous studies on preparation of solid dispersions have been published found that the solubility of poor water soluble drugs has been significantly improved by production of solid dispersions and in turn drug dissolution rate and bioavailability. However, the stability is one of the limitations that faced the solid dispersion which need to be solved and it will be issue that we will focus on in the present research.
One of the promising techniques to improve the bioavailability of poor soluble drugs (Class II) is to use solid dispersions as a drug delivery system which can be obtained by several methods; however, selecting one of these methods is very important which dependon the characters and the performance of the drugs and carriers. The three major methods are: melting methods, solvent evaporation methods, and melting solvent methods (Vilhelmsen, T.,2005). Moreover, this manufacturing process of solid dispersions can be divided into several techniques as shown in (Figure 1)
(Figure 1) Manufacturing processes of Solid Dispersions. (Ki Taek Kim 2011)
Selection of the API and the carrier (polymer) should be suitable with each other and it is very important issue; due to the dissolution behavior of the polymer is a domain factor that affects the solubility and dissolution rate of class II drugs which is insoluble in water. Moreover, drug-polymer interactions may affect the drug release. Therefore, drug-polymer system should be carefully considered when preparing solid dispersion (Ki Taek Kim2011)(Fumie Tanno 2004).
The polymer used in this research was Hydroxypropyl Methylcellulose Acetate Succinate HPMC-AS (LF grade) is a cellulous derivatives white to yellowish amorphous powder and has physiological compatibility; furthermore, it contains acetyl groups which have hydrophobic property and succinoyl groups which have hydrophilic property are introduced into hydroxyl groups of HPMC backbone as shown in (Figure 589) which offer important characters to the polymer.In other words; the organic acids (e.g. acetic and succinic acids) help to accelerate the drug release and to improve the dissolution rate due to Amphiphilic property.
Figure 589, HPMC-AS polymer (taken from supplier, Shin-Estu, Japan)
Moreover, HPMC-AS has a unique characteristic it can be dissolved in buffers of various PH values which can be controlled by changing the grades of HPMC-AS (Obara, S 1999); in other words, it can be controlled by changing the ratio of acetyl and succinoyl groups and the particle sizes as There are six grades of HPMC-AS which are divided according to their particle size and the chemical substitutions levels. However, HPMC-AS is surface active carrier which revealed that it may help to improve the stability of amorphous solid dispersion by inhibition the nucleation and agglomeration, hence it may prevent re-crystallization of the solid dispersion and become physical and chemical stable. (Pouton 2006)
As we know the amorphous form is not stable comparing to crystalline form because the tendency of the amorphous form to convert into crystalline form during producing of solid dispersion or storage; therefore, the dissolution rate and stability of solid dispersion would gradually decrease during storage time, thus affecting the bioavailability of the drug and limits its use. However, the present study may demonstrate extension in the stability of amorphous form significantly by preparing solid dispersion of Felodipine with HPMC-AS.
Therefore, the aim of the present research is to observe comparison of amorphous solid dispersion of Felodipine/HPMC-AS (API/Polymer) that produced by using two different pharmaceutical techniques the first one is category as melting methods(Hot Melt Extrusion) and the second one is category as melting solvent methods (Spray Drying); moreover, to determine if these techniques will affect the solubility of the class II drug (e.g. Felodipine) and whether they will influence the dissolution rate and the bioavailability of the drug; furthermore, to evaluate if these techniques will produce stable products by using HPMC-AS due to the amorphous forms are known to have low stability than crystalline forms stability. Therefore, the properties of formulations were studied by using thermal and analytical techniques which are used to evaluate the physicochemical characterization and the morphology of products; for example, differential scanning calorimetry (DSC), thermo-gravimetric Analysis (TGA) and X-ray diffraction (XRD); in addition, dissolution and stability study.
The reason for selecting these two techniques is because they are the most commercial scales present in pharmaceutical industry for producing solid dispersion.In addition, for making comparison between both of them and decide the best one for solid dispersion according to the results.
Hot Melt Extrusion
The simple definition of melting methods is when the physical mixture of drug and carrier is heated at specific temperature until melted then the molten mixture is cooled and solidification into desired shape.
In other words, Hot Melt Extrusion (HME) is essentially the same as the melting method; further, this process is widely used inrubber, plastic, and food industry. Recently, HME has found its way to enter the pharmaceutical industry and has been applied for manufacturing a variety of dosage formulations such as pellets, granules, tablets, implants, transdermal systems and suppositories. Therefore, HME in pharmaceutical meaning is the process that converting a raw materials (i.e. drugs, polymers or both of them) into a product having uniform shape and density by forcing these materials to pass through barrel area which has desired temperature then shaping the extrudes by using specific die.
For more understanding HME process, HME can be divided into four steps: (1) feeding mixture: in this step the powder mixture of API and polymer is feeding into heating barrels manually or by using auto-feeder after proper mixing (2) conveying of mass and entry into the die: this is the core of HME, because the physical mixture will transform into molten mixture (homogenous solid dispersion) of drug and polymer after blending inside the heating barrels by a single screw or co-rotating twin screw (rotating in the same direction) that in turn compress, mix and melt the mixture materials (3) flow throw the die: the molten mass pumps through the die which forms the extrudates into the required shape (4) exit from the die and down-stream processing: extrudates will be cooled then the collection will be shaping to fit the required uses(e.g. tablets, pellets or films).
However, in this study we used twin screw extruder because it possess many advantages over single screw; for example: shorter residence time between (5-10 mins) hence avoiding overheating, superior mixing because it consists of three section; feeding section, melting section and metering section as shown in (Figure ), versatility as the operating parameters can be adjusted easily during operation process. (Sarika Madana,2012)
Hot Melt ExtrusionHot Melt Extrusion process has many advantages which helped it to grow quickly in pharmaceutical applications. One of the major advantages compared to the traditional process is free solvent(i.e. anhydrous) process and oxygen may be omitted almost completely; therefore, suitable for moisture and oxygen sensitive drugs so prevent hydrolysis and oxidation; in addition, there is no needed for drying step and the operating parameters can be easily changed during processing, Moreover, the procedure is a fast continuous, one-step and simple process; also, HME provides good distributive and dispersive mixing which give homogenous distribution of drug within carrier (i.e. polymer). Furthermore, it improved product quality, reduced product variability and the residence time is short (2-10 mins) causing short thermal exposure of API permits processing of heat sensitive drugs. Additionally, HME helps to masking bitter taste of some APIs by using some polymers (e.g. HPMC). In addition, it enhances the bioavailability by improving the dissolution rate of poorly water soluble drugs by forming amorphous solid dispersion of drug in the polymer. Moreover, it has good yield percentage between (55-75 %). Finally it is green technology as no organic solvent is needed and are readily scalable. (Sarika Madana,2012)(JorgBreitenbach 2002) (E.I. Keleb 2004)(LienSaerens 2012)
However, HME also has certain challenges; for instance, high process knowledge required, high process temperature, reprocessing of materials is difficult, cleaning difficult, high energy input, high initial cost; however, all these limitations can be overcome once the desired parameters and the process are firmed up.(Sarika Madana,2012)(JorgBreitenbach 2002)
The steps of production solid dispersion using Hot Melt Extrusion is described in (Figure 2)
The second technique used to prepare solid dispersion in this study is spray drying which is a technique transforming liquid or slurry formations (e.g. solution, suspension or emulsions), which are obtained by dissolving APIs and excipients (e.g. polymer) in a suitable solvent (e.g. methanol or acetone), into dry powdered forms. (Masters 1985). Moreover, spray drying is one of the promising techniques which is widely used in pharmaceutical industry to increase the solubility and dissolution rate by preparing micro-particles of drug with polymer.
Spray drying process consist of four mainly steps as shown in (Figure 3): (1) feeding: after preparation the feedstock in flask then the feedstock is introducing into the spray dryer chamber at specific feeder speed (2) atomization: is the heart of any spray drying machine it helps to create the best condition for evaporation by breaking the solution up into small droplets which have diameter less than 100µm (3) droplets-gas contact and drying step: the atomized droplets reach the chamber so these droplets will be directly in contact with hot gas (e.g. Nitrogen which is inlet gas) providing heat required for rapid evaporation of more than 95 % of water from the droplets in only a fraction of a second after that as the solvent is removed from the dried droplets a high viscosity membrane forms on the outside of the droplets due to the film forming property of HPMC-AS. Furthermore, the drying step is very critical step as selecting proper conditions (e.g. inlet and outlet temperature, gas flow rates and atomizer pressure) effect directly on the speed of removing solvent from the droplets (4) separation: the dried droplets will be separated according to its size into different areas called cyclones or by using filter system which called scrubber; for example, Cyclon-1 will collect fine particles and Cyclon-2 will collect the very fine particles; moreover, the last chamber called Scrubber will collect ultra-fine particles. Therefore, the desired particles size is selected according to the type of the dosage form.
Furthermore, the reasons that make spray drying an attractive process nowadays due to it offers many advantages. For instance, it is a single-step, closed-system and continuous process as it is fully automated control system that allows direct monitoring and controlling parameters process simultaneously, also it can be designed to receive any capacity required (i.e. feeding rates can be range from a few pounds per hour to over 100 tons per hour) that mean it is scalable process range from small-scale production to large-scale commercial production; in addition, the designs of spray dryer give it ability to meet the various product specifications (i.e. the feedstock can be solution, slurry, paste, suspension, gel, emulsion or melt form). It is suitable with both heat-sensitive and heat-resistant products because the actual drying time of a droplet is very short as the solvent evaporated in less than few seconds it helps avoiding overheating. Moreover, the dried product can be nearly spherical particles in the form of powder, agglomerates or granules with large surface area and uniform particle size depending on the selected parameters (e.g. feeding rate, inlet and outlet temperature of air, atomizer pressure, viscosity and the physical and chemical properties of the feedstock). (Dwayne T 2008) (Gharsallaoui A 2007)( Renata Jachowicz 2008)( R. P. Patel2009) (Patel Tejas2012)( Pierre Lebrun 2012)
However, spray drying also has certain challenges; for instance, the equipment is very bulky and expensive, also low yield percentage between (30-55 %). Moreover, it has limited in producing particles with complex morphologies. Furthermore, large volumes of heated air pass through the Chamber without contacting a droplet; therefore, its thermal efficiency is low. ( R. P. Patel2009) (Patel Tejas2012)
MATERIALS AND METHODS:
Felodipine was purchase from Hubei MaxSource Chem Co., Ltd. (Wuhan City, China) and the material that has been used as polymer, which has two generic names was Hydroxypropyl Methylcellulose Acetate Succinate, JPE or Hypromellose Acetate Succinate, NF (HPMC-AS: Shin-Estu AQOAT®) with grade (LF) as shown in (Table 1),was obtained from (Shin-Estu Chemical Co., Tokyo, Japan). HPMC-AS is aqueous enteric coating agent and non-toxic material which has been used in pharmaceutical industry for many years. Acetone was purchased from Sigma-Aldrich Company Ltd. Gillingham, UK. All chemicals were used directly without further purification.
Table 1, Grades of HPMC-AS according to Accetyl and Succinoyl Group content
Preparation of Solid Dispersion
Three batches of drug and polymer mixture were prepared. Batch (No. 1) contains Felodipine/HPMC-AS 30 g (1:1 w/w) was mixed in a plastic bag for 10 min, bath (No. 2) contains Felodipine/HPMC-AS 30 g (1:2 w/w) was mixed in a plastic bag for 10 min and batch (No. 3) contains Felodipine/HPMC-AS 40 g (1:3 w/w) was mixed in a plastic bag for 10 min after that all these batches extruded using a hot melt extrusion,16 mm co-rotating twin screw extruder (Thermo Fisher Scientific, Germany) which has production range between (0.2-5 kg/h). In addition, the extruder barrel was divided into zones (2-10 zones); moreover, the temperature of each zone and die can be controlled separately. Furthermore, the process parameters were fixed for whole batches. The feeding rate into the melt extruder was approximately (4.5-5 g/m) and was manually due to small amount of batches. Screw speed was 100 rpm. Moreover, the temperature sequence was shown in (Table 2).
Table 2, Temperature sequence in hot melt extrusion for processing
In addition, we should wait about (5-10 min) between each batch to be sure all materials had been extruded, due to the residence time in the extruder was approximately (5-7 min), to prevent contamination between batches; moreover, the first product of each batch should be discarded. Finally, the melt extrudate was air cooled on a conveyor belt.
Shin-Estu Company supports us with cleaning material which is special for HPMC polymer; therefore, the cleaning issue becomes easier. However, the Temperature sequence for Cleaning was differ from the temperature of processing as was shown in (Table 3)
Table 3, Temperature sequence in hot melt extrusion for cleaning
Three batches of drug and polymer mixture were prepared. Batch (No.1) contains Felodipine/HPMC-AS 5 g (1:1 w/w 2.5/2.5 w/w) was dissolved in 200 ml of acetone, bath (No.2) contains Felodipine/HPMC-AS 7.5g (1:2 w/w 2.5-5 w/w) was dissolved in 200 ml of acetone and batch (No.3) contains Felodipine/HPMC-AS 10g (1:3 w/w 2.5-7.5 w/w) was also dissolved in 200 ml of acetone; in other words, Felodipine was dissolved in 100ml acetone and HPMC-AS was dissolved in 50ml acetone and was then stirred using magnetic stirrer until completely dissolution both solutions mixed together then the final 50 ml acetone was added. After that all batches spray dried using laboratory Spray Dryer (LU-228 Advanced® Labultima, Maharashtra, India) which accept solvent/aqueous Feeds with co-current Spray and has twin cyclons connected directly with N2 Inert Loop the reason for using Nitrogen as atomizing gas in spray drying process because acetone is flammable organic solvent and nitrogen is considered as an inlet gas. Moreover, the following spray drying conditions shown in (Table 4) were used:
Feed pump flow rate
Aspirator Flow rate
Up to +50 mm
Table 4, Spray Drying Conditions
Finally, spray dried powders were weighted and collected in capped glass vials.
Preparation of Physical Mixture
For comparison with solid dispersion physical Mixtures of Felodipine/HPMC-AS with three different ratio (1:1 w/w), (1:2 w/w) and (1:3 w/w) were prepared by mixing for 10 min in a mortar and pestle.
The study of in vitro dissolution test was performed using two types of dissolution medium the first medium was phosphate buffer solution PH 6.8 and the other one was Phosphate Buffer solution PH 6.8 with 1% sodium dodecyl sulfate SDS as a surfactant; however, both mediums should maintained at 37 ± 5 ËšC to simulated the nature of intestine â€¦... .Consists of six vessels and the paddle speed was set at 50 rpm. Moreover, powder samples of solid dispersions (1:1, 1:2 and 1:3) produced by HME and Spray drying equivalent to 25 mg of Felodipine were added to 900 ml dissolution medium which maintained at 37 ± 5 ËšC. In addition, the physical mixtures (1:1, 1:2 and 1:3) were studied and added to 900ml dissolution medium also to compare the results with the results of solid dispersions. Furthermore, 5ml samples were withdrawn according to this times intervals from each vessel (5, 10, 15, 20, 30, 45, 60, 75, 90, 135, 345, 405 min) and filtered through 0.45 µm syringe filters (Millex®HA, MCE membrane, Millipore co., Carrigtwohill, Ireland) then replaced with an equal volume of fresh media. Then the amount of drug release was determined using (UV-Vis) spectroscopy at wavelength 364 nm â€¦.
Thermogravimetric Analysis (TGA)
The study was performed on samples of Felodipine and HPMC-AS separately by using TGA Q5000® system (TA instruments Inc., New Castle, USA) to understand and determine the decomposition temperature of the API and polymer. About 5-10 mg samples were heated in open platinum pans from 10 ËšC to 500 ËšC, and then the experimental data were collected and analyzed using TA Universal Analysis 2000 software Version 4.7A (TA instruments Inc., New Castle, USA). Nitrogen was used as a purge gas at a flow rate of 25 ml/min.
Figure 400, Thermogravimetric Analysis (TGA) Q5000
Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry experiments were used to determine and measure the changing in thermal properties (e.g. glass transition temperature and melting point) of the prepared solid dispersions and physical mixtures by using DSC Q2000® instrument (TA instruments Inc., New Castle, USA). About 2-5 mg Samples were accurately weighed into aluminum pans with a pinhole lid and hermetically crimped. The samples were heated under nitrogen environment in a temperature range between 25 ËšC to 250 ËšC with heating rates of 5ËšC/min. Nitrogen was used as a purge gas at a flow rate of 50 ml/min.
Figure 500, Differential Scanning Calorimetry (DSC) Q2000
X-ray powder diffraction (pXRD)
The X-ray powder diffraction was performed using D8- ADVANCE® (Bruker AXS Inc., Madison, USA). The samples were placed on the sample holder (0.5 mm deep) and the amount needed was approximately 500 mg to occupy the holder and form a thin layer of the sample powder. The X-ray was obtain by a copper radiation source Cu KÎ± (Î»=1.54056 Å) with generator voltage of 40 kV and current of 40 mA. Moreover, the samples were scanned on continuous detector scan mode over the diffraction angle (2Î¸) range of 2 Ëš <2Î¸ <60Ëš (with a 2Î¸ step size of 0.01220Ëš and at scan speed of 1s/step) at ambient condition, while sample rotation was off. Finally, the results were analyzed and collected using EVA DIFFRACplus® software (Bruker AXS Inc., Madison, USA).
Approximately 1-4 g sample size of each of the solid dispersion was collected in capped glass bottles and placed inside controlled humidity and temperature stability room (Memmert HPP-108®, Memmert Co. Germany) with pre-equilibrated condition to 40ËšC/75% RH. During the course of study a small amount of samples were withdrawn for each bottle at specific time interval (i.e. each 10 days) for examination and characterization by using DSC and pXRD before replace the bottles back into the stability room.
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