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Conversion of solid dispersion prepared by acid–base interaction into free-flowing and tabletable powder by using Neusilin® US2
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IJP 14696 1–9 International Journal of Pharmaceutics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
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Pharmaceutical nanotechnology
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Conversion of solid dispersion prepared by acid–base interaction into free-flowing and tabletable powder by using Neusilin1 US2
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4 Q1
Ankita Shah, Abu T.M. Serajuddin *
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Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 November 2014 Received in revised form 13 January 2015 Accepted 23 February 2015 Available online xxx
A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin1 US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40 C/75% RH and 25 C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared. ã 2015 Published by Elsevier B.V.
Keywords: Haloperidol Weak organic acids Poorly water-soluble drug Supersolubilization Amorphous solid dispersion Neusilin1 US2
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1. Introduction
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The dissolution rate is the rate limiting step for absorption of BCS (Biopharmaceutical Classification Systems) class II drugs having low aqueous solubility and high gastrointestinal membrane permeability. Solid dispersion (SD), where a relatively waterinsoluble drug is dispersed either molecularly or in the amorphous state in water-soluble carriers, is commonly studied to enhance dissolution rates for such drugs (Leuner and Dressman, 2000; Vasanthavada et al., 2008). However, there are some major challenges in the formulation of SDs of drugs as dosage forms, which include inadequate drug-carrier miscibility, need of organic solvents to dissolve drug and carrier during preparation, difficulty in manufacturing and scale up, physical instability due to recrystallization of drug from solubilized or amorphous states, and thermal degradation during the manufacture of SD, especially when a hot melt process is applied (Serajuddin, 1999; Vasanthavada et al., 2008). For these reasons, there is a limited number of drug products prepared by SD in the market despite extensive research in the field for over half a century (Chiou and Riegelman, 1971; Sekiguchi and Obi, 1961).
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* Corresponding author. Tel.: +1 718 990 7822; fax: +1 718 990 1877. E-mail address: [email protected] (A.T.M. Serajuddin).
Singh et al. (2013) reported a novel method of preparing SD by using acid–base interaction in an aqueous media. When a basic drug haloperidol was added to aqueous solutions of malic acid, tartaric acid and citric acid, the solubility of haloperidol increased greatly. For example, in presence of malic acid, one gram of solution contained as high as 0.33 g of haloperidol, the other two components being 0.37 mg of malic acid and 0.30 g of water. Thus, the haloperidol to acid ratio in the aqueous solution was close to 1. Similarly, high aqueous solubility of haloperidol was also obtained in presence of tartaric acid and citric acid. The organic acids were selected such that they were water-soluble and they would not form salts with haloperidol. Since extremely high solubility of drug was obtained simply by dissolving a poorly water-soluble basic drug in aqueous solutions of weak organic acids, without necessitating the addition of any organic solvents, complexing agents, etc., the authors called the phenomenon supersolubilization by acid–base interaction. When the concentrated solutions were dried, amorphous SDs of the drug in organic acids were formed, where the drug neither formed crystalline salts with acids nor did they convert back to the crystalline free base form. The drug remained amorphous even after exposure to different accelerated stability conditions, such as high humidity, temperature fluctuation, etc. Despite the relative simplicity, one disadvantage of preparing amorphous SDs by acid–base supersolubilization was that the
http://dx.doi.org/10.1016/j.ijpharm.2015.02.060 0378-5173/ ã 2015 Published by Elsevier B.V.
Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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material produced, especially at high drug to organic acid ratios, were viscous, semisolid, gummy and sticky, and could not be compressed into tablets or filled in hard gelatin capsules as powders. Because of high viscosity, the SD also did not readily redisperse in dissolution media and there was incomplete drug release. Initial attempts to improve material quality and dissolution rate by using hydrophilic carriers such as polyvinyl pyrrolidone, polyethylene glycols (PEGs), poloxamer 188, etc. were unsuccessful. Then, further studies were conducted to improve processibility and dissolution rate by using waterinsoluble carriers with high surface area. The present report describes how the SD prepared by acid–base interaction can be converted from the viscous semisolid state to free-flowing and tabletable powders by adsorption onto the silicate, Neusilin1 US2. Haloperidol was selected as the model drug because it had previously been studied extensively for its pHdependent solubility and dissolution rate (Greco and Bogner, 2012; Greco et al., 2011; Li et al., 2005a,b). It was also the subject of supersolubilization by acid–base interaction by Singh et al. (2013). The primary objective of the present investigation was to develop a novel technology for the development of SD formulation of a poorly water-soluble basic drug irrespective of the dose of model drug used. To demonstrate the general application of the technology, haloperidol tablets were, therefore, prepared at the relatively high 150-mg strength rather than at its clinical doses of 5 and 10 mg. Neusilin1 US2 consists of amorphous microporous granular particles of magnesium aluminometasilicate with the particle Q3 diameter of 60–120 mm and a high specific surface area of 300 m2/g (Fuji Chemical Industry, 2010). Gupta et al. (2001) used Neusilin1 US2 to enhance bulk properties and dissolution rate of SDs. It has also been used to convert drugs into their amorphous state and then stabilize them physically from conversation into crystalline forms (Bahl et al., 2008; Gupta et al., 2003; Miura et al., 2010). More recently, Gumaste et al. (2013a,b) investigated flow and tableting properties of several different silicates after adsorption of lipid-based formulations onto them and observed that Neusilin1 US2 provided the most suitable morphology for the adsorption of liquids. The silicate retained acceptable tableting properties even when mixed with lipids at 1:1 w/w ratio. It was, therefore, of interest that Neusilin1 US2 was tried to adsorb SDs prepared by supersolubilization and convert them into freeflowing and tabletable powders.
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2. Materials and methods
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2.1. Materials
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Haloperidol free base was purchased from Spectrum Chemicals (New Brunswick, NJ, USA). Malic acid, tartaric acid and citric acid (monohydrate) were purchased from VWR International (Radnor, PA, USA). Neusilin1 US2 was supplied by Fuji Health Science (Burlington, NJ, USA) and Kollidon1 CL was obtained from BASF
Corp. (Tarrytown, NY, USA). Lactose (a-lactose monohydrate) was supplied by Meggel (Wasserburg, Germany). Magnesium stearate was purchased from Sigma–Aldrich (St. Louis, MO, USA). All solvents and other chemicals used were of analytical reagent grade or better. Deionized water was used throughout the study.
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2.2. Methods
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2.2.1. Loading of aqueous solutions of haloperidol and weak acids onto Neusilin1 US2 Weights and molar ratios of haloperidol to weak organic acids used are given in Table 1. Depending on the solubility of weak organic acids in water, attempts were made to select as high molar ratios of haloperidol to weak acids as possible (Singh et al., 2013). The amount of Neusilin1 US2 was selected such that the ratio of solid dispersion (drug plus acid) to Neusilin1 US2 was 1.5:1 w/w. The aqueous solution of each weak organic acid was first prepared in a beaker and haloperidol was then dissolved in the solution (Singh et al., 2013). In each experiment, 3 g of water was usually used to prepare a solution of acid and haloperidol as per Table 1. The required amounts of Neusilin1 US2 was then added to the aqueous solution of weak organic acid and haloperidol in the beaker and mixed using a spatula until all the liquid adsorbed onto the silicate and apparently homogenous granules were obtained. The granules were placed on petri dishes and subjected to vacuum drying at 30 in Hg for 6 h at 30 C. The drying time was selected based on preliminary studies where no change in weight was observed when the materials were further dried for 24 or 48 h.
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2.2.2. Characterization of dried powders Before any analysis, dried granules were grinded using mortar and pestle, passed through #40 mesh sieve, and blended (Twin shell dry blender, PA, USA) for 10–15 min to assure uniformity of powders.
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2.2.2.1. Assay of powders. Accurately weighed amounts of powders (50 mg each) were dispersed in volumetric flasks using 60:40 v/v mixture of methanol and deionized water as the solvent. All flasks were sonicated for 20 min to ensure complete release and solubilization of drug. Since Neusilin1 US2 was insoluble in the solvent, all dispersions were filtered through 0.45 mm polypropylene syringe filters (VWR Scientific, Bridgeport, NJ, USA) and then analyzed by HPLC system (HP1100 series, Agilent Technologies, Wilmington, DE, USA) after appropriate dilutions. The assay conditions for HPLC were: C8 Waters XBridge column 3.5 mm, 4.6 mm 150 mm; mobile phase of 60:40 v/v mixture of methanol and monobasic potassium phosphate (0.05 M, pH 2.5 to 3); 0.75 mL/min flow rate; and lmax of 247 nm.
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2.2.2.2. Thermogravimetric analysis (TGA). TGA of powders was performed using a Q50 thermogravimetric analyzer (TA Instruments, DE, USA) to determine moisture content in dried powders. For each analysis, 5 to 10 mg of sample was weighed
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Table 1 Relative amounts of haloperidol, weak organic acids, water and Neusilin1 US2 used in the preparation of solid dispersions (SD). Weak acid used
Malic acid Tartaric acid Citric acid a b
Relative weights of different components b
Drug load in haloperidol-weak acid solid dispersion 1
Haloperidol
Acid
Water
Neusilin
(g)
(g)
(g)
(g)
% w/w
Molar ratio
0.81 0.60 0.22
1 1 1
1 1 1
1.21 1.07 0.81
44.8 37.5 18.0
0.29:1 0.24:1 0.12:1
US2
Drug load after adsorption of SD onto Neusilin1 US2a (% w/w)
Haloperidol/Acid
26.8 22.5 10.8
The ratio of haloperidol-weak acid solid dispersion to Neusilin1 US2 was kept constant at 1.5:1 w/w. Water was removed by drying.
Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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into a tared crucible and then heated from 25 to 250 C at the heating rate of 10 C/min under a constant nitrogen purge. 2.2.2.3. Differential scanning calorimetry (DSC). Thermal behavior of samples was analyzed using modulated differential scanning calorimeter (Q200 DSC; TA Instruments, DE, USA) equipped with a refrigerated cooling accessory. Briefly, a sample was weighed (5 to 10 mg) and sealed in aluminum pan with a pin hole on the cover and then heated from 10 to 200 C at a ramp rate of 5 C/min and modulation rate of 1 C every minute. In order to separate the reversible phenomenon, such as the glass transition temperature, from the nonreversible phenomenon of the sample, such as the water loss, the reversible heat flow was used. 2.2.2.4. Powder X-ray diffraction analysis (PXRD). To determine the physical state of haloperidol and weak acids in powders, PXRD was performed at room temperature using a powder X-ray diffractometer (XRD-6000; Shimadzu, Kyoto, Japan). The diffraction patterns were measured with a voltage of 40 kV and a current of 30 mA over a 2u range of 10–60 using a step size of 0.02 at a scan speed of 2 /min. 2.2.2.5. Density and flow properties of powders. Various compendial methods (USP/NF, 2007) were used to determine powder flow properties, such as bulk density, tapped density, Carr ’s Compressibility Index (Carr, 1965), Hausner ratio, etc. Four grams of each powder were placed in a 25-mL of graduated glass cylinder to measure bulk and tapped density. For the measurement of tapped density, the cylinder was tapped on Vanderkamp tap density tester (Vankel Industries, Edison, NJ, USA) until no further change in volume of powder was observed. The bulk density of powder was calculated as the ratio of weight to volume of the powder before tapping, and the tapped density was calculated as the ratio of the weight of powder to its final tapped volume. 2.2.3. Tablet formulations The compositions of tablets prepared by using the powder formulations containing three different acids are given in Table 2. Lactose, Kollidon1 CL and magnesium stearate were added externally to solid dispersion, respectively, as filler, disintegrant and lubricant. Initially, 5% w/w Kollidon1 CL was used in the tablets. However, it was observed that the tablets disintegrated slowly by erosion in 10–15 min when their dissolution tests were conducted in the pH 2 medium (0.01 N HCl), thus slowing the release of haloperidol from tablets. The disintegration of tablets was also slow when other disintegrants were used at the 5% w/w level. When the concentration of Kollidon1 CL was increased to 10% w/w, the tablets disintegrated in <5 min during dissolution
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testing. For the preparation of tablets, approximately 5 g of powders, except magnesium stearate, was mixed together in a 20-mL scintillation vial by attaching it to a blender (Twin shell dry blender, PA, USA) at 25 rpm for 15 min. Magnesium stearate was Q5 then added to the powder and the blending was continued for one more minute. Tablets were compressed at either 2000 or 3000 pounds of pressure using 11.6 mm flat face punches (Natoli Engineering, Saint Charles, MO, USA) on a single punch Carver Press assembly (Carver Inc., Wabash, IN, USA). The dwell time during compression was 10 s.
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2.2.4. Tensile strength of tablets A Vanderkamp tablet hardness tester (Vanderkamp 1000) was used to determine hardness of tablets prepared. Tablet dimensions were then used to calculate the tensile strengths (r) of tablets using the following equations:
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r¼
Haloperidol Malic acid Tartaric acid Citric acid Neusilin1 US2 Solid dispersion powderb Lactose Disintegrant Lubricant Total weight
Tablet with malic acid
195 196 197 198 199 200 201 202
204 205 206 207
2F
pDT
where F is the breaking force, and D and T are, respectively, diameter and thickness (Fell and Newton, 1970).
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2.2.5. Dissolution studies
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2.2.5.1. Step-dissolution study of tablets. Since haloperidol exhibits pH-dependent solubility, a multi-step dissolution test was conducted to mimic pH conditions of the gastrointestinal fluids. An USP dissolution apparatus II (Distek Inc., North Brunswick, NJ, USA) at 37 0.2 C and 50 rpm was used for this purpose. The amount of haloperidol in each test sample was kept constant at 0.15 g (one tablet containing malic or tartaric acid; 2 tablets containing citric acid). In step 1, 250 mL of 0.01 N HCl (pH 2) was used as the dissolution medium and 4 mL of aliquot was withdrawn at each of 5, 15, 30, 60, 90 and 120 min time points. Immediately after the 120-min sampling, the step 2 dissolution was conducted, where the pH was changed to 4.5 by adding the appropriate amount 1.0 N NaOH and the dissolution was continued up to 150 min. The volume of NaOH solution added was noted to correct for the volume of the dissolution medium. The dissolution at step 2 was followed by the step 3, where the pH was adjusted similarly to 6.8 and samples were withdrawn at 180 and 240 min time points. Aliquots withdrawn at each time point were replenished by adding equivalent volume of appropriate dissolution medium. All aliquots were first filtered through 5 mm syringe filter to remove coarse Neusilin1 US2 particles. Then the same filtrate was filtered again through 0.45 mm polypropylene syringe filter for quantification of drug content by HPLC after appropriate dilution.
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Table 2 Composition of tablet formulations for dissolution testing. Components
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Tablet with citric acida
Tablet with tartaric acid
Weight (g)
Weight %
Weight (g)
Weight %
Weight (g)
Weight %
0.15 0.19 – – 0.22 0.56 0.022 0.065 0.0033 0.650
23.1 29.2 – – 33.8 86.2 3.4 10.0 0.5 100
0.15 – 0.25 – 0.27 0.67 0.020 0.077 0.0039 0.770
19.5 – 32.5 – 35.0 87.0 2.5 10.0 0.5 100
0.075 – – 0.34 0.28 0.70 0.021 0.080 0.004 0.800
9.4 – – 42.5 35.0 87.5 2.6 10.0 0.5 100
a The composition of citric acid tablet formulation is given for one tablet containing 0.075 g of haloperidol. For dissolution testing, two such tablets were used. In all cases, haloperidol plus weak acid to Neusilin1 US2 was kept at 1.5:1 w/w. b Haloperidol-weak acid-Neusilin1 US2 solid dispersion powders were mixed with lactose, disintegrant (Kollidon1 CL) and lubricant (magnesium stearate) before compression into tablets.
Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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Fig. 1. Haloperidol-malic acid 0.81:1 w/w; molar ratio 0.29:1 solid dispersion (A) without Neusilin1 US2 and (B) with Neusilin1 US2.
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2.2.5.2. Dissolution study in pH 6.8 phosphate buffer. Separately, the dissolution test of tablets was also conducted in the pH 6.8 buffer, without first testing them at pH 2 and 4.5. Since the drug is practically insoluble at this pH, this test would indicate whether there was any possible supersaturation of haloperidol in the dissolution medium from different formulations. The dissolution test using 250 mL of buffer was continued for 3 h. Other test conditions were similar to those described above for the multi-step dissolution.
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2.2.6. Stability studies To determine whether any conversion of haloperidol and acids used from their amorphous state to crystalline form would occur upon storage, all dried powders were stored at 25 C/60% RH and 40 C/75% RH for 9 months. The relative humidity and temperature of test chambers were monitored using hygrometers (Daigger Scientific, Vernon Hills, IL, USA). DSC and PXRD were used to analyze samples at the end of 9 months.
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3. Results and discussion
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3.1. Conversion of solid dispersion into free-flowing powders As mentioned earlier, the SD prepared by the acid–base interaction resulted in semisolid sticky material. Fig. 1 shows that the gummy material may be converted to powders by adsorption onto Neusilin1 US2. The figure shows the results for the haloperidol SD in malic acid only, where the drug load in absence of Neusilin1 US2 was 44.8% w/w, while it was 26.8% w/w when the silicate was added to convert the material into powder. The results, therefore, show that powdered SD containing high drug loads (>25%) may be obtained by this method. Table 1 shows that relatively high drug loads may also be obtained in dry powder formulations containing tartaric acid (22.5% w/w) and citric acid (10.8% w/w). These results show that not only amorphous SD with high drug load may be obtained by acid–base supersolubilization, the material may also be converted into powders by adsorption onto Neusilin1 US2. The ratio of the SD (i.e., drug plus weak organic acid) to Neusilin1 US2 in the final powder was 1.5 to 1 w/w, and the results show that even such a high amount of semisolid sticky material (60% w/w) may be adsorbed onto Neusilin1 US2 (40% w/w) to produce powders. The adsorption of such high amounts of semisolid sticky SD and yet forming free-flowing powder were possible due to certain unique physicochemical properties of by Neusilin1 US2, such as its mesoporous nature, relatively high particle size, and high specific surface area. By studying scanning electron microscopic (SEM) images of different silicates before and after adsorption of oily liquids, Gumaste et al. (2013a) observed that the liquid adsorb deep into the pores of relatively large particles of Neusilin1 US2, while the liquid remains mostly on the surface of other silicates. As shown in Table 1, the drug load obtained by different acids in the powders may, however, vary depending on aqueous solubility and solubilizing
capacity of acids used. Further studies were conducted to characterize the powders for their suitability to develop tablets.
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3.2. Assay of powders
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Three representative samples were analyzed for drug content from each batch of powders produced using different acids and the silicate. The % drug content was found to be within the range of 90–110% w/w of the theoretical amount present, indicating good content uniformity of powders.
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3.3. Thermogravimetric analysis
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Fig. 2 gives the TGA scans of the three powders containing different acids along with Neusilin1 US2. The TGA scan of the neat Neusilin1 US2 is also included. Due to its high porosity and high specific surface area, there is adsorbed water onto Neusilin1 US2, which dehydrates upon heating. In case of the neat silicate, there was a rapid weight loss between 25 and 45 C, while the weight loss was gradual in formulations with haloperidol and acids. For the purpose of comparison, the weight losses from Neusilin1 US2 and the three powder formulations in the temperature range of 25–120 C were compared based on the assumption that most of the loosely held water would evaporate out at this temperature. Neusilin1 US2 showed 7.5% weight loss at this temperature, while dried powders showed weight loss in the range of 3.4–5.4% w/w. These results indicate that the powders were in equilibrium with atmospheric moisture at room temperature and any weight loss at higher temperature was due to possible dehydration of adsorbed water.
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Fig. 2. TGA analysis of powders containing (a) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-citric acid and Neusilin1 US2 solid dispersion, and (d) neat Neusilin1 US2 after 4 h of vacuum drying.
Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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3.4. Differential scanning calorimetry
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The results of the DSC analysis of various components of formulations, such as Neusilin1 US2, haloperidol, malic acid, tartaric acid and citric acid as well as the dried powders containing SDs of haloperidol in weak organic acids that were loaded onto Neusilin1 US2 are shown in Fig. 3. Haloperidol showed crystalline endothermic peak at around 151 C. Similarly, the crystalline nature of malic, tartaric and citric acids was confirmed by melting peak at around 132 C, 173 C and 154 C, respectively. The neat Neusilin1 US2 and all powders showed complete absence of any endothermic peak. These results indicate that haloperidol and the acids turned amorphous in the powders.
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3.5. Powder X-ray diffraction analysis (PXRD)
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PXRD patterns of neat Neusilin1 US2, haloperidol, malic acid, tartaric acid, citric acid and haloperidol-weak acid SD loaded onto Neusilin1 US2 are shown in Fig. 4. The results are in agreement with the results of DSC analysis, showing crystalline peaks for haloperidol and weak organic acids (malic, tartaric and citric acids). As Neusilin1 US2 was amorphous, it showed only halos and there were no PXRD peaks. The dry powders of drug formulations also did not show any PXRD peaks, thus confirming the conversion of the drug and acids into the amorphous form in SDs.
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3.6. Density and flow properties of powders
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It was reported earlier by Gumaste et al. (2013a,b) that Neusilin1 US2 has excellent flow, density and compressibility that are suitable for tableting. It showed acceptable tableting properties even after the loading of lipids onto it. The properties of different powder formulations containing haloperidol, weak organic acids and Neusilin1 US2 are given in Table 3. The density of Neusilin1 US2 increased by factors of 3–5 when the SDs of haloperidol in different acids were loaded onto it. The formulations containing malic acid and tartaric acid exhibited fair Carr’s compressibility indices and Hausner ratios, while the values were excellent for the citric acid formulation. Overall, the results indicate that tablets with acceptable physical properties may be obtained by using any of these formulations.
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Fig. 3. DSC analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (d) neat Neusilin1 US2, (e) citric acid, (f) tartaric acid, (g) malic acid, and (h) haloperidol.
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Fig. 4. PXRD analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (d) neat Neusilin1 US2, (e) citric acid, (f) tartaric acid, (g) malic acid, and (h) haloperidol.
3.7. Tensile strength of tablets
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Tensile strength is a very important parameter to define the mechanical behavior of tablets. Tablets should possess enough strength to withstand various stress encountered during processing and handling. Tensile strength values in excess of 1 MPa are generally considered acceptable for tablets (Amidon et al., 2009). Tablet tensile strengths versus compression pressures of different formulations are shown in Fig. 5. At the 3000 pounds of pressure, the tensile strength of tablets containing malic acid and tartaric acids were 1.6 MPa, whereas it was 0.6 MPa for the citric acid formulation. When the compression pressure was increased from 3000 to 4000 pounds, the tensile strength of each tablet formulation was either equal to or in excess of 1 MPa.
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3.8. Dissolution studies
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3.8.1. Step-dissolution study of tablets Haloperidol is a weakly basic drug demonstrating pH-dependent solubility (Li et al., 2005b). When taken orally, it has a high aqueous solubility at the stomach pH condition of 1–3 and then the solubility decreases as the pH increases during its passage through the intestinal tract. The compound is practically insoluble at the intestinal pH condition of 5.5–7.5. Therefore, a step dissolution study at pH 2, 4.5 and 6.8 was conducted for the tablets prepared ( Table 2), and the results are shown in Fig. 6A and B. Fig. 6A shows step-dissolution results of tablet formulations containing haloperidol and weak acids loaded on Neusilin1 US2, while Fig. 6B serves as the control as it gives step-dissolution results of SD preparations containing haloperidol and acids only and no Neusilin1 US2 was added. The amounts of drug and acids were kept constant in both cases. All tablets prepared using powders containing Neusilin1 US2 disintegrated rapidly during dissolution testing in <5 min. Over 90% of drug dissolved at pH 2 in <30 min (Fig. 6A). In contrast, in absence of Neusilin1 US2, the formulations showed only
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Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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Table 3 Density and flow properties of neat Neusilin1 US2 and haloperidol-weak acid-Neusilin1 US2 solid dispersions (n = 4).
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Sample Name
Density (g/cc) Bulk
Neat Neusilin1 US2 Malic acid Tartaric acid Citric acid
0.17 0.48 0.51 0.78
Carr’s compressibility index
Hausner ratio
Tapped
Value
Classification
Value
Classification
0.19 0.58 0.63 0.86
15 17 18 09
Good Fair Fair Excellent
1.17 1.20 1.22 1.10
Good Fair Fair Excellent
40–60% drug release in 30 min (Fig. 6B). The later formulations containing malic acid, tartaric acid and citric acid (no Neusilin1 US2 present) showed only 62, 50 and 67% of drug release, respectively, even after 2 h of dissolution testing at pH 2 (Singh et al., 2013). Thus, these results demonstrate a dramatic increase in dissolution rate of SDs prepared by using haloperidol and weak organic acids when Neusilin1 US2 was added to them. This is due to the difference in physical properties of two types of formulations. In absence of Neusilin1 US2, SDs were viscous and gummy in nature, which did not disperse completely in aqueous media resulting in incomplete release. On the other hand, tablets prepared from free-flowing powders containing Neusilin1 US2 disintegrated in <5 min and showed fast and complete release of drug. Thus, the present study shows the importance of dispersion of dosage form in dissolution media. It was also observed in the multi-step dissolution test that the drug did not precipitate out from the dissolution medium in any of the formulations despite much decrease in solubility of haloperidol at pH 4.5 and 6.8 (Li et al., 2005b). At pH 6.8, the equilibrium solubility of haloperidol is 60 mg/mL, and, therefore, about 10% of a 0.15-g haloperidol tablet could theoretically dissolve in 250 mL of pH 6.8 dissolution medium used. However, Fig. 6A shows that 90% remained in solution at 4 h. This was because the SD produced a very highly supersaturated solution and there was a slow induction time for crystallization of haloperidol once it went into solution. 3.8.2. Dissolution study in pH 6.8 phosphate buffer In multi-step dissolution testing mentioned above, solid dispersion tablets of haloperidol were first dissolved at pH 2, where haloperidol has a good solubility. However, it is possible that the tablet may first encounter a higher pH due to individual variation in the human gastrointestinal pH condition and the difference in gastric residence time. For this reason, the dissolution
Fig. 5. Tensile strength of tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions at two different compression pressure (n = 3).
of 0.15-g haloperidol solid dispersion tablets were also studied in 250 mL of a pH 6.8 aqueous buffer. This would show how the drug would dissolve if the pH is high and, consequently, the drug solubility is low. Fig. 7 shows dissolution profiles of haloperidol at pH 6.8 from three formulations containing malic, tartaric or citric acids along with Neusilin1 US2. It was observed that around 70% drug dissolved within 15 min when tablets containing malic acid and citric acid were dispersed in the dissolution medium. There was no further increase in drug release with time from the malic acid-containing formulation, while the drug release from the formulation containing citric acid increased to 90%. From the formulation with tartaric acid, the drug release was 50% in 15 min, which increased to 70% at 30 min. Thus, among the three formulations, the one with citric acid showed highest amount of drug. Formulations containing malic and tartaric acids showed some drop in drug concentration after 30 min, reaching a level of 50% at 180 min. The formulation containing citric acid showed more than 95% drug in solution even at the end of 180 min of dissolution testing at pH 6.8. In a separate study, it was observed that there was only 6% haloperidol dissolution when 0.15 g of haloperidol powder was added to 250 mL of the pH 6.8 buffer (data not shown). Thus, supersaturation with a 12-fold increase in concentration could be obtained from formulations containing malic and tartaric acids, and there was a 16-fold increase in concentration from the formulation with citric acid. These results may indicate that even if a SD formulation containing acids bypasses the low gastric pH, the drug may still dissolve and can form supersaturated solutions. The difference in dissolution profiles of haloperidol from formulations containing malic, tartaric and citric acids may possibly be attributed to the difference in amounts of acids present in the tablets. It may be observed in Table 2 that the amount of acid in a tablet relative to the amount haloperidol present is higher in case of the formulation containing citric acid as compared to those with malic and tartaric acids. The microenvironmental pH was possibly modulated differently depending on the amounts of acids present tablets. It should, however, be noted here that the pH of the dissolution medium was maintained within the range of 6.6–6.8 throughout the dissolution testing.
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3.9. Stability studies
451
Conventionally, solid state stability testing is carried out at accelerated stability conditions using elevated temperature, high humidity or both. Being high-energy solids, amorphous drugs have natural tendency to convert back to their respective low-energy and more stable crystalline forms. It is well established that the amorphous to crystalline conversion is accelerated in the presence of sorbed moisture (Hancock et al., 1995). Therefore, any potential crystallization of haloperidol in the powders was monitored on a monthly basis by DSC and PXRD analyses by exposing samples to 40 C/75% RH and 25 C/60% RH. There was no crystallization of drug even after exposure to these conditions for 9 months. The results of the PXRD analysis of powders are shown in Fig. 8. The results are in agreement with the postulation by Singh et al. (2013) that the drug would not crystallize out from SDs prepared by the
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Fig. 6. Step-dissolution profiles of (A) tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions, (B) haloperidol-weak organic acid solid dispersions without Neusilin1 US2 (6B is reproduced from Singh et al., 2013 with permission, and is used for comparison with 6A). In all formulations, 0.15 g of haloperidol was used.
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Fig. 7. Dissolution profiles of tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions in pH 6.8 phosphate buffer.
Fig. 8. PXRD analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion after testing at 40 C/75% RH for 9 month stability.
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acid–base supersolubilization technique as the drug would neither form crystalline salts nor would it convert to the free base in presence of excess acids.
469
4. Summary and concluding remarks
470
Many different strategies for preparing SDs of poorly watersoluble drugs have been reported in the literature. The most common approach has been the conversion crystalline drugs to their amorphous forms in presence of water-soluble polymers or other carriers. However, such formulations may encounter physical stability issues due to the reconversion of amorphous materials to their crystalline forms, thus defeating the purpose of preparing amorphous SDs. There are also major manufacturing difficulties with such formulations. Singh et al. (2013) reported a novel supersolubilization technique to greatly increase solubility and dissolution rates of a basic drug, haloperidol, by incorporating such weak organic acids
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as malic acid, tartaric acid and citric acid that would not form salts with the compound. The increase in the aqueous solubility of haloperidol in presence of these acids was as high as 300,000 to 500,000 times greater than that of the free base solubility of 2.5 mg/mL. Physically stable SDs of haloperidol in weak organic acids, with drug loads as high as 40–50% w/w, were formed when the concentrated solutions of haloperidol and week organic acids were dried. The dissolution rate of haloperidol increased due to its very high drug solubility when SDs came in contact with aqueous media. One major disadvantage of the SD system developed by Singh et al. (2013) was that, when the drug load was high, the SD could exist as a viscous semisolid mass that was not processable into tablets. The material also did not easily disperse in aqueous media and, therefore, could exhibit incomplete drug release. In the present investigation, the issues with processing and dissolution of haloperidol SDs prepared by using the acid–base supersolubilization technique were resolved by adsorbing them on Neusilin1 US2, a metalosilicate. Due to its unique physicochemical properties, the silicate adsorbed aqueous solutions of haloperidol and weak organic acids into its pores and, upon drying, formed powders instead of sticky semisolid mass. The powders exhibited good flow properties as well as requisite properties for tableting. When tablets prepared by using the powders were subjected to multi-step dissolution testing under different gastrointestinal pH conditions, they dispersed completely in <5 min at pH 2 and complete drug release was obtained in <30 min. Supersaturated solutions were formed under the intestinal pH condition of 6.8. Further studies in our laboratory using other drugs showed that the supersolubilization technology and the conversion of material into dry solids by adsorption onto Neusilin1 US2 has general application in the development of SD systems for both basic and acidic drugs.
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References
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Amidon, G.E., Secreast, P.J., Mudie, D., 2009. Particle, powder, and compact characterization. In: Qiu, Y., Chen, Y., Zhang, G.G.Z. (Eds.), Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice. Academic Press, San Diego, pp. 163–186. Bahl, D., Hudak, J., Bogner, R.H., 2008. Comparison of the ability of various pharmaceutical silicates to amorphize and enhance dissolution of indomethacin upon co-grinding. Pharm. Dev. Technol. 13, 255–269. Carr, R.L., 1965. Evaluating flow properties of solids. Chem. Eng. 72, 163–168. Chiou, W.L., Riegelman, S., 1971. Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci. 60, 1281–1302. Fell, J., Newton, J., 1970. Determination of tablet strength by the diametralcompression test. J. Pharm. Sci. 59, 688–691. Fuji Chemical Industry Co., Ltd., 2010. General Properties of Neusilin. Available from: http://www.neusilin.com/product/general_properties.php. Greco, K., Bogner, R., 2012. Solution-mediated phase transformation: significance during dissolution and implications for bioavailability. J. Pharm. Sci. 101, 2996– 3018. Greco, K., Mcnamara, D.P., Bogner, R., 2011. Solution-mediated phase transformation of salts during dissolution: investigation using haloperidol as a model drug. J. Pharm. Sci. 100, 2755–2768. Gumaste, S.G., Pawlak, S.A., Dalrymple, D.M., Nider, C.J., Trombetta, L.D., Serajuddin, A.T.M., 2013a. Development of solid SEDDS, IV: effect of adsorbed lipid and surfactant on tableting properties and surface structures of different silicates. Pharm. Res. 30, 3170–3185. Gumaste, S.G., Dalrymple, D.M., Serajuddin, A.T.M., 2013b. Development of solid SEDDS V: compaction and drug release properties of tablets prepared by adsorbing lipid-based AT onto Neusilin1 US2. Pharm. Res. 30, 3186– 3199. Gupta, M.K., Goldman, D., Bogner, R.H., Tseng, Y., 2001. Enhanced drug dissolution and bulk properties of solid dispersions granulated with a surface adsorbent. Pharm. Dev. Technol. 6, 563–572. Gupta, M.K., Vanwert, A., Bogner, R.H., 2003. Formation of physically stable amorphous drugs by milling with Neusilin. J. Pharm. Sci. 92, 536–551. Hancock, B.C., Shamblin, S.L., Zografi, G., 1995. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm. Res. 12, 799–806. Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 50, 47–60.
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Li, S., Doyle, P., Metz, S., Royce, A.E., Serajuddin, A.T.M., 2005a. Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug. J. Pharm. Sci. 94, 2224–2231. Li, S., Wong, S., Sethia, S., Almoazen, H., Joshi, Y.M., Serajuddin, A.T.M., 2005b. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm. Res. 22, 628–635. Miura, H., Kanebako, M., Shirai, H., Nakao, H., Inagi, T., Terada, K., 2010. Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug K-832, by adsorption onto porous silica using supercritical carbon dioxide. Eur. J. Pharm. Biopharm. 76, 215–221.
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Sekiguchi, K., Obi, N., 1961. Studies on absorption of eutectic mixture: I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull. 9, 866–872. Serajuddin, A.T.M.,1999. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88, 1058–1066. Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A. T.M., 2013. Supersolubilization and amorphization of a model basic drug haloperidol, by interaction with weak acid. Pharm. Res. 30, 1561–1573. USP/NF (The United States Pharmacopeia 30/National Formulary 25), Powder Flow <1174>, United States Pharmacopeial Convention. MD, USA: Rockville, 2007.
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Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
1
Pharmaceutical nanotechnology
2
Conversion of solid dispersion prepared by acid–base interaction into free-flowing and tabletable powder by using Neusilin1 US2
3
4 Q1
Ankita Shah, Abu T.M. Serajuddin *
5
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 November 2014 Received in revised form 13 January 2015 Accepted 23 February 2015 Available online xxx
A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin1 US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40 C/75% RH and 25 C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared. ã 2015 Published by Elsevier B.V.
Keywords: Haloperidol Weak organic acids Poorly water-soluble drug Supersolubilization Amorphous solid dispersion Neusilin1 US2
6
1. Introduction
7
The dissolution rate is the rate limiting step for absorption of BCS (Biopharmaceutical Classification Systems) class II drugs having low aqueous solubility and high gastrointestinal membrane permeability. Solid dispersion (SD), where a relatively waterinsoluble drug is dispersed either molecularly or in the amorphous state in water-soluble carriers, is commonly studied to enhance dissolution rates for such drugs (Leuner and Dressman, 2000; Vasanthavada et al., 2008). However, there are some major challenges in the formulation of SDs of drugs as dosage forms, which include inadequate drug-carrier miscibility, need of organic solvents to dissolve drug and carrier during preparation, difficulty in manufacturing and scale up, physical instability due to recrystallization of drug from solubilized or amorphous states, and thermal degradation during the manufacture of SD, especially when a hot melt process is applied (Serajuddin, 1999; Vasanthavada et al., 2008). For these reasons, there is a limited number of drug products prepared by SD in the market despite extensive research in the field for over half a century (Chiou and Riegelman, 1971; Sekiguchi and Obi, 1961).
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Q2
* Corresponding author. Tel.: +1 718 990 7822; fax: +1 718 990 1877. E-mail address: [email protected] (A.T.M. Serajuddin).
Singh et al. (2013) reported a novel method of preparing SD by using acid–base interaction in an aqueous media. When a basic drug haloperidol was added to aqueous solutions of malic acid, tartaric acid and citric acid, the solubility of haloperidol increased greatly. For example, in presence of malic acid, one gram of solution contained as high as 0.33 g of haloperidol, the other two components being 0.37 mg of malic acid and 0.30 g of water. Thus, the haloperidol to acid ratio in the aqueous solution was close to 1. Similarly, high aqueous solubility of haloperidol was also obtained in presence of tartaric acid and citric acid. The organic acids were selected such that they were water-soluble and they would not form salts with haloperidol. Since extremely high solubility of drug was obtained simply by dissolving a poorly water-soluble basic drug in aqueous solutions of weak organic acids, without necessitating the addition of any organic solvents, complexing agents, etc., the authors called the phenomenon supersolubilization by acid–base interaction. When the concentrated solutions were dried, amorphous SDs of the drug in organic acids were formed, where the drug neither formed crystalline salts with acids nor did they convert back to the crystalline free base form. The drug remained amorphous even after exposure to different accelerated stability conditions, such as high humidity, temperature fluctuation, etc. Despite the relative simplicity, one disadvantage of preparing amorphous SDs by acid–base supersolubilization was that the
http://dx.doi.org/10.1016/j.ijpharm.2015.02.060 0378-5173/ ã 2015 Published by Elsevier B.V.
Please cite this article in press as: Shah, A., Serajuddin, A.T.M., Conversion of solid dispersion prepared by acid–base interaction into freeflowing and tabletable powder by using Neusilin1 US2. Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.02.060
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material produced, especially at high drug to organic acid ratios, were viscous, semisolid, gummy and sticky, and could not be compressed into tablets or filled in hard gelatin capsules as powders. Because of high viscosity, the SD also did not readily redisperse in dissolution media and there was incomplete drug release. Initial attempts to improve material quality and dissolution rate by using hydrophilic carriers such as polyvinyl pyrrolidone, polyethylene glycols (PEGs), poloxamer 188, etc. were unsuccessful. Then, further studies were conducted to improve processibility and dissolution rate by using waterinsoluble carriers with high surface area. The present report describes how the SD prepared by acid–base interaction can be converted from the viscous semisolid state to free-flowing and tabletable powders by adsorption onto the silicate, Neusilin1 US2. Haloperidol was selected as the model drug because it had previously been studied extensively for its pHdependent solubility and dissolution rate (Greco and Bogner, 2012; Greco et al., 2011; Li et al., 2005a,b). It was also the subject of supersolubilization by acid–base interaction by Singh et al. (2013). The primary objective of the present investigation was to develop a novel technology for the development of SD formulation of a poorly water-soluble basic drug irrespective of the dose of model drug used. To demonstrate the general application of the technology, haloperidol tablets were, therefore, prepared at the relatively high 150-mg strength rather than at its clinical doses of 5 and 10 mg. Neusilin1 US2 consists of amorphous microporous granular particles of magnesium aluminometasilicate with the particle Q3 diameter of 60–120 mm and a high specific surface area of 300 m2/g (Fuji Chemical Industry, 2010). Gupta et al. (2001) used Neusilin1 US2 to enhance bulk properties and dissolution rate of SDs. It has also been used to convert drugs into their amorphous state and then stabilize them physically from conversation into crystalline forms (Bahl et al., 2008; Gupta et al., 2003; Miura et al., 2010). More recently, Gumaste et al. (2013a,b) investigated flow and tableting properties of several different silicates after adsorption of lipid-based formulations onto them and observed that Neusilin1 US2 provided the most suitable morphology for the adsorption of liquids. The silicate retained acceptable tableting properties even when mixed with lipids at 1:1 w/w ratio. It was, therefore, of interest that Neusilin1 US2 was tried to adsorb SDs prepared by supersolubilization and convert them into freeflowing and tabletable powders.
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2. Materials and methods
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2.1. Materials
96 97 98 99 100
Haloperidol free base was purchased from Spectrum Chemicals (New Brunswick, NJ, USA). Malic acid, tartaric acid and citric acid (monohydrate) were purchased from VWR International (Radnor, PA, USA). Neusilin1 US2 was supplied by Fuji Health Science (Burlington, NJ, USA) and Kollidon1 CL was obtained from BASF
Corp. (Tarrytown, NY, USA). Lactose (a-lactose monohydrate) was supplied by Meggel (Wasserburg, Germany). Magnesium stearate was purchased from Sigma–Aldrich (St. Louis, MO, USA). All solvents and other chemicals used were of analytical reagent grade or better. Deionized water was used throughout the study.
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2.2. Methods
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2.2.1. Loading of aqueous solutions of haloperidol and weak acids onto Neusilin1 US2 Weights and molar ratios of haloperidol to weak organic acids used are given in Table 1. Depending on the solubility of weak organic acids in water, attempts were made to select as high molar ratios of haloperidol to weak acids as possible (Singh et al., 2013). The amount of Neusilin1 US2 was selected such that the ratio of solid dispersion (drug plus acid) to Neusilin1 US2 was 1.5:1 w/w. The aqueous solution of each weak organic acid was first prepared in a beaker and haloperidol was then dissolved in the solution (Singh et al., 2013). In each experiment, 3 g of water was usually used to prepare a solution of acid and haloperidol as per Table 1. The required amounts of Neusilin1 US2 was then added to the aqueous solution of weak organic acid and haloperidol in the beaker and mixed using a spatula until all the liquid adsorbed onto the silicate and apparently homogenous granules were obtained. The granules were placed on petri dishes and subjected to vacuum drying at 30 in Hg for 6 h at 30 C. The drying time was selected based on preliminary studies where no change in weight was observed when the materials were further dried for 24 or 48 h.
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2.2.2. Characterization of dried powders Before any analysis, dried granules were grinded using mortar and pestle, passed through #40 mesh sieve, and blended (Twin shell dry blender, PA, USA) for 10–15 min to assure uniformity of powders.
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2.2.2.1. Assay of powders. Accurately weighed amounts of powders (50 mg each) were dispersed in volumetric flasks using 60:40 v/v mixture of methanol and deionized water as the solvent. All flasks were sonicated for 20 min to ensure complete release and solubilization of drug. Since Neusilin1 US2 was insoluble in the solvent, all dispersions were filtered through 0.45 mm polypropylene syringe filters (VWR Scientific, Bridgeport, NJ, USA) and then analyzed by HPLC system (HP1100 series, Agilent Technologies, Wilmington, DE, USA) after appropriate dilutions. The assay conditions for HPLC were: C8 Waters XBridge column 3.5 mm, 4.6 mm 150 mm; mobile phase of 60:40 v/v mixture of methanol and monobasic potassium phosphate (0.05 M, pH 2.5 to 3); 0.75 mL/min flow rate; and lmax of 247 nm.
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2.2.2.2. Thermogravimetric analysis (TGA). TGA of powders was performed using a Q50 thermogravimetric analyzer (TA Instruments, DE, USA) to determine moisture content in dried powders. For each analysis, 5 to 10 mg of sample was weighed
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Table 1 Relative amounts of haloperidol, weak organic acids, water and Neusilin1 US2 used in the preparation of solid dispersions (SD). Weak acid used
Malic acid Tartaric acid Citric acid a b
Relative weights of different components b
Drug load in haloperidol-weak acid solid dispersion 1
Haloperidol
Acid
Water
Neusilin
(g)
(g)
(g)
(g)
% w/w
Molar ratio
0.81 0.60 0.22
1 1 1
1 1 1
1.21 1.07 0.81
44.8 37.5 18.0
0.29:1 0.24:1 0.12:1
US2
Drug load after adsorption of SD onto Neusilin1 US2a (% w/w)
Haloperidol/Acid
26.8 22.5 10.8
The ratio of haloperidol-weak acid solid dispersion to Neusilin1 US2 was kept constant at 1.5:1 w/w. Water was removed by drying.
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into a tared crucible and then heated from 25 to 250 C at the heating rate of 10 C/min under a constant nitrogen purge. 2.2.2.3. Differential scanning calorimetry (DSC). Thermal behavior of samples was analyzed using modulated differential scanning calorimeter (Q200 DSC; TA Instruments, DE, USA) equipped with a refrigerated cooling accessory. Briefly, a sample was weighed (5 to 10 mg) and sealed in aluminum pan with a pin hole on the cover and then heated from 10 to 200 C at a ramp rate of 5 C/min and modulation rate of 1 C every minute. In order to separate the reversible phenomenon, such as the glass transition temperature, from the nonreversible phenomenon of the sample, such as the water loss, the reversible heat flow was used. 2.2.2.4. Powder X-ray diffraction analysis (PXRD). To determine the physical state of haloperidol and weak acids in powders, PXRD was performed at room temperature using a powder X-ray diffractometer (XRD-6000; Shimadzu, Kyoto, Japan). The diffraction patterns were measured with a voltage of 40 kV and a current of 30 mA over a 2u range of 10–60 using a step size of 0.02 at a scan speed of 2 /min. 2.2.2.5. Density and flow properties of powders. Various compendial methods (USP/NF, 2007) were used to determine powder flow properties, such as bulk density, tapped density, Carr ’s Compressibility Index (Carr, 1965), Hausner ratio, etc. Four grams of each powder were placed in a 25-mL of graduated glass cylinder to measure bulk and tapped density. For the measurement of tapped density, the cylinder was tapped on Vanderkamp tap density tester (Vankel Industries, Edison, NJ, USA) until no further change in volume of powder was observed. The bulk density of powder was calculated as the ratio of weight to volume of the powder before tapping, and the tapped density was calculated as the ratio of the weight of powder to its final tapped volume. 2.2.3. Tablet formulations The compositions of tablets prepared by using the powder formulations containing three different acids are given in Table 2. Lactose, Kollidon1 CL and magnesium stearate were added externally to solid dispersion, respectively, as filler, disintegrant and lubricant. Initially, 5% w/w Kollidon1 CL was used in the tablets. However, it was observed that the tablets disintegrated slowly by erosion in 10–15 min when their dissolution tests were conducted in the pH 2 medium (0.01 N HCl), thus slowing the release of haloperidol from tablets. The disintegration of tablets was also slow when other disintegrants were used at the 5% w/w level. When the concentration of Kollidon1 CL was increased to 10% w/w, the tablets disintegrated in <5 min during dissolution
3
testing. For the preparation of tablets, approximately 5 g of powders, except magnesium stearate, was mixed together in a 20-mL scintillation vial by attaching it to a blender (Twin shell dry blender, PA, USA) at 25 rpm for 15 min. Magnesium stearate was Q5 then added to the powder and the blending was continued for one more minute. Tablets were compressed at either 2000 or 3000 pounds of pressure using 11.6 mm flat face punches (Natoli Engineering, Saint Charles, MO, USA) on a single punch Carver Press assembly (Carver Inc., Wabash, IN, USA). The dwell time during compression was 10 s.
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2.2.4. Tensile strength of tablets A Vanderkamp tablet hardness tester (Vanderkamp 1000) was used to determine hardness of tablets prepared. Tablet dimensions were then used to calculate the tensile strengths (r) of tablets using the following equations:
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r¼
Haloperidol Malic acid Tartaric acid Citric acid Neusilin1 US2 Solid dispersion powderb Lactose Disintegrant Lubricant Total weight
Tablet with malic acid
195 196 197 198 199 200 201 202
204 205 206 207
2F
pDT
where F is the breaking force, and D and T are, respectively, diameter and thickness (Fell and Newton, 1970).
209 208 210
2.2.5. Dissolution studies
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2.2.5.1. Step-dissolution study of tablets. Since haloperidol exhibits pH-dependent solubility, a multi-step dissolution test was conducted to mimic pH conditions of the gastrointestinal fluids. An USP dissolution apparatus II (Distek Inc., North Brunswick, NJ, USA) at 37 0.2 C and 50 rpm was used for this purpose. The amount of haloperidol in each test sample was kept constant at 0.15 g (one tablet containing malic or tartaric acid; 2 tablets containing citric acid). In step 1, 250 mL of 0.01 N HCl (pH 2) was used as the dissolution medium and 4 mL of aliquot was withdrawn at each of 5, 15, 30, 60, 90 and 120 min time points. Immediately after the 120-min sampling, the step 2 dissolution was conducted, where the pH was changed to 4.5 by adding the appropriate amount 1.0 N NaOH and the dissolution was continued up to 150 min. The volume of NaOH solution added was noted to correct for the volume of the dissolution medium. The dissolution at step 2 was followed by the step 3, where the pH was adjusted similarly to 6.8 and samples were withdrawn at 180 and 240 min time points. Aliquots withdrawn at each time point were replenished by adding equivalent volume of appropriate dissolution medium. All aliquots were first filtered through 5 mm syringe filter to remove coarse Neusilin1 US2 particles. Then the same filtrate was filtered again through 0.45 mm polypropylene syringe filter for quantification of drug content by HPLC after appropriate dilution.
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Table 2 Composition of tablet formulations for dissolution testing. Components
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Tablet with citric acida
Tablet with tartaric acid
Weight (g)
Weight %
Weight (g)
Weight %
Weight (g)
Weight %
0.15 0.19 – – 0.22 0.56 0.022 0.065 0.0033 0.650
23.1 29.2 – – 33.8 86.2 3.4 10.0 0.5 100
0.15 – 0.25 – 0.27 0.67 0.020 0.077 0.0039 0.770
19.5 – 32.5 – 35.0 87.0 2.5 10.0 0.5 100
0.075 – – 0.34 0.28 0.70 0.021 0.080 0.004 0.800
9.4 – – 42.5 35.0 87.5 2.6 10.0 0.5 100
a The composition of citric acid tablet formulation is given for one tablet containing 0.075 g of haloperidol. For dissolution testing, two such tablets were used. In all cases, haloperidol plus weak acid to Neusilin1 US2 was kept at 1.5:1 w/w. b Haloperidol-weak acid-Neusilin1 US2 solid dispersion powders were mixed with lactose, disintegrant (Kollidon1 CL) and lubricant (magnesium stearate) before compression into tablets.
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Fig. 1. Haloperidol-malic acid 0.81:1 w/w; molar ratio 0.29:1 solid dispersion (A) without Neusilin1 US2 and (B) with Neusilin1 US2.
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2.2.5.2. Dissolution study in pH 6.8 phosphate buffer. Separately, the dissolution test of tablets was also conducted in the pH 6.8 buffer, without first testing them at pH 2 and 4.5. Since the drug is practically insoluble at this pH, this test would indicate whether there was any possible supersaturation of haloperidol in the dissolution medium from different formulations. The dissolution test using 250 mL of buffer was continued for 3 h. Other test conditions were similar to those described above for the multi-step dissolution.
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2.2.6. Stability studies To determine whether any conversion of haloperidol and acids used from their amorphous state to crystalline form would occur upon storage, all dried powders were stored at 25 C/60% RH and 40 C/75% RH for 9 months. The relative humidity and temperature of test chambers were monitored using hygrometers (Daigger Scientific, Vernon Hills, IL, USA). DSC and PXRD were used to analyze samples at the end of 9 months.
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3. Results and discussion
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3.1. Conversion of solid dispersion into free-flowing powders As mentioned earlier, the SD prepared by the acid–base interaction resulted in semisolid sticky material. Fig. 1 shows that the gummy material may be converted to powders by adsorption onto Neusilin1 US2. The figure shows the results for the haloperidol SD in malic acid only, where the drug load in absence of Neusilin1 US2 was 44.8% w/w, while it was 26.8% w/w when the silicate was added to convert the material into powder. The results, therefore, show that powdered SD containing high drug loads (>25%) may be obtained by this method. Table 1 shows that relatively high drug loads may also be obtained in dry powder formulations containing tartaric acid (22.5% w/w) and citric acid (10.8% w/w). These results show that not only amorphous SD with high drug load may be obtained by acid–base supersolubilization, the material may also be converted into powders by adsorption onto Neusilin1 US2. The ratio of the SD (i.e., drug plus weak organic acid) to Neusilin1 US2 in the final powder was 1.5 to 1 w/w, and the results show that even such a high amount of semisolid sticky material (60% w/w) may be adsorbed onto Neusilin1 US2 (40% w/w) to produce powders. The adsorption of such high amounts of semisolid sticky SD and yet forming free-flowing powder were possible due to certain unique physicochemical properties of by Neusilin1 US2, such as its mesoporous nature, relatively high particle size, and high specific surface area. By studying scanning electron microscopic (SEM) images of different silicates before and after adsorption of oily liquids, Gumaste et al. (2013a) observed that the liquid adsorb deep into the pores of relatively large particles of Neusilin1 US2, while the liquid remains mostly on the surface of other silicates. As shown in Table 1, the drug load obtained by different acids in the powders may, however, vary depending on aqueous solubility and solubilizing
capacity of acids used. Further studies were conducted to characterize the powders for their suitability to develop tablets.
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3.2. Assay of powders
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Three representative samples were analyzed for drug content from each batch of powders produced using different acids and the silicate. The % drug content was found to be within the range of 90–110% w/w of the theoretical amount present, indicating good content uniformity of powders.
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3.3. Thermogravimetric analysis
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Fig. 2 gives the TGA scans of the three powders containing different acids along with Neusilin1 US2. The TGA scan of the neat Neusilin1 US2 is also included. Due to its high porosity and high specific surface area, there is adsorbed water onto Neusilin1 US2, which dehydrates upon heating. In case of the neat silicate, there was a rapid weight loss between 25 and 45 C, while the weight loss was gradual in formulations with haloperidol and acids. For the purpose of comparison, the weight losses from Neusilin1 US2 and the three powder formulations in the temperature range of 25–120 C were compared based on the assumption that most of the loosely held water would evaporate out at this temperature. Neusilin1 US2 showed 7.5% weight loss at this temperature, while dried powders showed weight loss in the range of 3.4–5.4% w/w. These results indicate that the powders were in equilibrium with atmospheric moisture at room temperature and any weight loss at higher temperature was due to possible dehydration of adsorbed water.
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Fig. 2. TGA analysis of powders containing (a) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-citric acid and Neusilin1 US2 solid dispersion, and (d) neat Neusilin1 US2 after 4 h of vacuum drying.
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3.4. Differential scanning calorimetry
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The results of the DSC analysis of various components of formulations, such as Neusilin1 US2, haloperidol, malic acid, tartaric acid and citric acid as well as the dried powders containing SDs of haloperidol in weak organic acids that were loaded onto Neusilin1 US2 are shown in Fig. 3. Haloperidol showed crystalline endothermic peak at around 151 C. Similarly, the crystalline nature of malic, tartaric and citric acids was confirmed by melting peak at around 132 C, 173 C and 154 C, respectively. The neat Neusilin1 US2 and all powders showed complete absence of any endothermic peak. These results indicate that haloperidol and the acids turned amorphous in the powders.
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3.5. Powder X-ray diffraction analysis (PXRD)
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PXRD patterns of neat Neusilin1 US2, haloperidol, malic acid, tartaric acid, citric acid and haloperidol-weak acid SD loaded onto Neusilin1 US2 are shown in Fig. 4. The results are in agreement with the results of DSC analysis, showing crystalline peaks for haloperidol and weak organic acids (malic, tartaric and citric acids). As Neusilin1 US2 was amorphous, it showed only halos and there were no PXRD peaks. The dry powders of drug formulations also did not show any PXRD peaks, thus confirming the conversion of the drug and acids into the amorphous form in SDs.
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3.6. Density and flow properties of powders
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It was reported earlier by Gumaste et al. (2013a,b) that Neusilin1 US2 has excellent flow, density and compressibility that are suitable for tableting. It showed acceptable tableting properties even after the loading of lipids onto it. The properties of different powder formulations containing haloperidol, weak organic acids and Neusilin1 US2 are given in Table 3. The density of Neusilin1 US2 increased by factors of 3–5 when the SDs of haloperidol in different acids were loaded onto it. The formulations containing malic acid and tartaric acid exhibited fair Carr’s compressibility indices and Hausner ratios, while the values were excellent for the citric acid formulation. Overall, the results indicate that tablets with acceptable physical properties may be obtained by using any of these formulations.
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Fig. 3. DSC analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (d) neat Neusilin1 US2, (e) citric acid, (f) tartaric acid, (g) malic acid, and (h) haloperidol.
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Fig. 4. PXRD analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion, (d) neat Neusilin1 US2, (e) citric acid, (f) tartaric acid, (g) malic acid, and (h) haloperidol.
3.7. Tensile strength of tablets
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Tensile strength is a very important parameter to define the mechanical behavior of tablets. Tablets should possess enough strength to withstand various stress encountered during processing and handling. Tensile strength values in excess of 1 MPa are generally considered acceptable for tablets (Amidon et al., 2009). Tablet tensile strengths versus compression pressures of different formulations are shown in Fig. 5. At the 3000 pounds of pressure, the tensile strength of tablets containing malic acid and tartaric acids were 1.6 MPa, whereas it was 0.6 MPa for the citric acid formulation. When the compression pressure was increased from 3000 to 4000 pounds, the tensile strength of each tablet formulation was either equal to or in excess of 1 MPa.
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3.8. Dissolution studies
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3.8.1. Step-dissolution study of tablets Haloperidol is a weakly basic drug demonstrating pH-dependent solubility (Li et al., 2005b). When taken orally, it has a high aqueous solubility at the stomach pH condition of 1–3 and then the solubility decreases as the pH increases during its passage through the intestinal tract. The compound is practically insoluble at the intestinal pH condition of 5.5–7.5. Therefore, a step dissolution study at pH 2, 4.5 and 6.8 was conducted for the tablets prepared ( Table 2), and the results are shown in Fig. 6A and B. Fig. 6A shows step-dissolution results of tablet formulations containing haloperidol and weak acids loaded on Neusilin1 US2, while Fig. 6B serves as the control as it gives step-dissolution results of SD preparations containing haloperidol and acids only and no Neusilin1 US2 was added. The amounts of drug and acids were kept constant in both cases. All tablets prepared using powders containing Neusilin1 US2 disintegrated rapidly during dissolution testing in <5 min. Over 90% of drug dissolved at pH 2 in <30 min (Fig. 6A). In contrast, in absence of Neusilin1 US2, the formulations showed only
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Table 3 Density and flow properties of neat Neusilin1 US2 and haloperidol-weak acid-Neusilin1 US2 solid dispersions (n = 4).
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Sample Name
Density (g/cc) Bulk
Neat Neusilin1 US2 Malic acid Tartaric acid Citric acid
0.17 0.48 0.51 0.78
Carr’s compressibility index
Hausner ratio
Tapped
Value
Classification
Value
Classification
0.19 0.58 0.63 0.86
15 17 18 09
Good Fair Fair Excellent
1.17 1.20 1.22 1.10
Good Fair Fair Excellent
40–60% drug release in 30 min (Fig. 6B). The later formulations containing malic acid, tartaric acid and citric acid (no Neusilin1 US2 present) showed only 62, 50 and 67% of drug release, respectively, even after 2 h of dissolution testing at pH 2 (Singh et al., 2013). Thus, these results demonstrate a dramatic increase in dissolution rate of SDs prepared by using haloperidol and weak organic acids when Neusilin1 US2 was added to them. This is due to the difference in physical properties of two types of formulations. In absence of Neusilin1 US2, SDs were viscous and gummy in nature, which did not disperse completely in aqueous media resulting in incomplete release. On the other hand, tablets prepared from free-flowing powders containing Neusilin1 US2 disintegrated in <5 min and showed fast and complete release of drug. Thus, the present study shows the importance of dispersion of dosage form in dissolution media. It was also observed in the multi-step dissolution test that the drug did not precipitate out from the dissolution medium in any of the formulations despite much decrease in solubility of haloperidol at pH 4.5 and 6.8 (Li et al., 2005b). At pH 6.8, the equilibrium solubility of haloperidol is 60 mg/mL, and, therefore, about 10% of a 0.15-g haloperidol tablet could theoretically dissolve in 250 mL of pH 6.8 dissolution medium used. However, Fig. 6A shows that 90% remained in solution at 4 h. This was because the SD produced a very highly supersaturated solution and there was a slow induction time for crystallization of haloperidol once it went into solution. 3.8.2. Dissolution study in pH 6.8 phosphate buffer In multi-step dissolution testing mentioned above, solid dispersion tablets of haloperidol were first dissolved at pH 2, where haloperidol has a good solubility. However, it is possible that the tablet may first encounter a higher pH due to individual variation in the human gastrointestinal pH condition and the difference in gastric residence time. For this reason, the dissolution
Fig. 5. Tensile strength of tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions at two different compression pressure (n = 3).
of 0.15-g haloperidol solid dispersion tablets were also studied in 250 mL of a pH 6.8 aqueous buffer. This would show how the drug would dissolve if the pH is high and, consequently, the drug solubility is low. Fig. 7 shows dissolution profiles of haloperidol at pH 6.8 from three formulations containing malic, tartaric or citric acids along with Neusilin1 US2. It was observed that around 70% drug dissolved within 15 min when tablets containing malic acid and citric acid were dispersed in the dissolution medium. There was no further increase in drug release with time from the malic acid-containing formulation, while the drug release from the formulation containing citric acid increased to 90%. From the formulation with tartaric acid, the drug release was 50% in 15 min, which increased to 70% at 30 min. Thus, among the three formulations, the one with citric acid showed highest amount of drug. Formulations containing malic and tartaric acids showed some drop in drug concentration after 30 min, reaching a level of 50% at 180 min. The formulation containing citric acid showed more than 95% drug in solution even at the end of 180 min of dissolution testing at pH 6.8. In a separate study, it was observed that there was only 6% haloperidol dissolution when 0.15 g of haloperidol powder was added to 250 mL of the pH 6.8 buffer (data not shown). Thus, supersaturation with a 12-fold increase in concentration could be obtained from formulations containing malic and tartaric acids, and there was a 16-fold increase in concentration from the formulation with citric acid. These results may indicate that even if a SD formulation containing acids bypasses the low gastric pH, the drug may still dissolve and can form supersaturated solutions. The difference in dissolution profiles of haloperidol from formulations containing malic, tartaric and citric acids may possibly be attributed to the difference in amounts of acids present in the tablets. It may be observed in Table 2 that the amount of acid in a tablet relative to the amount haloperidol present is higher in case of the formulation containing citric acid as compared to those with malic and tartaric acids. The microenvironmental pH was possibly modulated differently depending on the amounts of acids present tablets. It should, however, be noted here that the pH of the dissolution medium was maintained within the range of 6.6–6.8 throughout the dissolution testing.
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3.9. Stability studies
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Conventionally, solid state stability testing is carried out at accelerated stability conditions using elevated temperature, high humidity or both. Being high-energy solids, amorphous drugs have natural tendency to convert back to their respective low-energy and more stable crystalline forms. It is well established that the amorphous to crystalline conversion is accelerated in the presence of sorbed moisture (Hancock et al., 1995). Therefore, any potential crystallization of haloperidol in the powders was monitored on a monthly basis by DSC and PXRD analyses by exposing samples to 40 C/75% RH and 25 C/60% RH. There was no crystallization of drug even after exposure to these conditions for 9 months. The results of the PXRD analysis of powders are shown in Fig. 8. The results are in agreement with the postulation by Singh et al. (2013) that the drug would not crystallize out from SDs prepared by the
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Fig. 6. Step-dissolution profiles of (A) tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions, (B) haloperidol-weak organic acid solid dispersions without Neusilin1 US2 (6B is reproduced from Singh et al., 2013 with permission, and is used for comparison with 6A). In all formulations, 0.15 g of haloperidol was used.
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Fig. 7. Dissolution profiles of tablet formulations containing haloperidol-weak organic acid and Neusilin1 US2 solid dispersions in pH 6.8 phosphate buffer.
Fig. 8. PXRD analysis of powders containing (a) haloperidol-citric acid and Neusilin1 US2 solid dispersion, (b) haloperidol-tartaric acid and Neusilin1 US2 solid dispersion, (c) haloperidol-malic acid and Neusilin1 US2 solid dispersion after testing at 40 C/75% RH for 9 month stability.
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acid–base supersolubilization technique as the drug would neither form crystalline salts nor would it convert to the free base in presence of excess acids.
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4. Summary and concluding remarks
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Many different strategies for preparing SDs of poorly watersoluble drugs have been reported in the literature. The most common approach has been the conversion crystalline drugs to their amorphous forms in presence of water-soluble polymers or other carriers. However, such formulations may encounter physical stability issues due to the reconversion of amorphous materials to their crystalline forms, thus defeating the purpose of preparing amorphous SDs. There are also major manufacturing difficulties with such formulations. Singh et al. (2013) reported a novel supersolubilization technique to greatly increase solubility and dissolution rates of a basic drug, haloperidol, by incorporating such weak organic acids
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as malic acid, tartaric acid and citric acid that would not form salts with the compound. The increase in the aqueous solubility of haloperidol in presence of these acids was as high as 300,000 to 500,000 times greater than that of the free base solubility of 2.5 mg/mL. Physically stable SDs of haloperidol in weak organic acids, with drug loads as high as 40–50% w/w, were formed when the concentrated solutions of haloperidol and week organic acids were dried. The dissolution rate of haloperidol increased due to its very high drug solubility when SDs came in contact with aqueous media. One major disadvantage of the SD system developed by Singh et al. (2013) was that, when the drug load was high, the SD could exist as a viscous semisolid mass that was not processable into tablets. The material also did not easily disperse in aqueous media and, therefore, could exhibit incomplete drug release. In the present investigation, the issues with processing and dissolution of haloperidol SDs prepared by using the acid–base supersolubilization technique were resolved by adsorbing them on Neusilin1 US2, a metalosilicate. Due to its unique physicochemical properties, the silicate adsorbed aqueous solutions of haloperidol and weak organic acids into its pores and, upon drying, formed powders instead of sticky semisolid mass. The powders exhibited good flow properties as well as requisite properties for tableting. When tablets prepared by using the powders were subjected to multi-step dissolution testing under different gastrointestinal pH conditions, they dispersed completely in <5 min at pH 2 and complete drug release was obtained in <30 min. Supersaturated solutions were formed under the intestinal pH condition of 6.8. Further studies in our laboratory using other drugs showed that the supersolubilization technology and the conversion of material into dry solids by adsorption onto Neusilin1 US2 has general application in the development of SD systems for both basic and acidic drugs.
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References
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Li, S., Doyle, P., Metz, S., Royce, A.E., Serajuddin, A.T.M., 2005a. Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug. J. Pharm. Sci. 94, 2224–2231. Li, S., Wong, S., Sethia, S., Almoazen, H., Joshi, Y.M., Serajuddin, A.T.M., 2005b. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm. Res. 22, 628–635. Miura, H., Kanebako, M., Shirai, H., Nakao, H., Inagi, T., Terada, K., 2010. Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug K-832, by adsorption onto porous silica using supercritical carbon dioxide. Eur. J. Pharm. Biopharm. 76, 215–221.
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Sekiguchi, K., Obi, N., 1961. Studies on absorption of eutectic mixture: I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull. 9, 866–872. Serajuddin, A.T.M.,1999. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88, 1058–1066. Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A. T.M., 2013. Supersolubilization and amorphization of a model basic drug haloperidol, by interaction with weak acid. Pharm. Res. 30, 1561–1573. USP/NF (The United States Pharmacopeia 30/National Formulary 25), Powder Flow <1174>, United States Pharmacopeial Convention. MD, USA: Rockville, 2007.
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