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1
Development of Solid Dispersion Systems of Dapivirine to Enhance its Solubility Adinarayana Gorajana1, Chan Chiew Ying1, Yeen Shuang1, Pooi Fong1, Zhi Tan1, Jyoti Gupta2, Meghna Talekar2, Manisha Sharma2 and Sanjay Garg2,3* 1
School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia; 2School of Pharmacy, University Of Auckland, Auckland, New Zealand; 3School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia Abstract: Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powderX-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drugexcipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug.
Keywords: HIV, Dapivirine, Dissolution rate, Microbicides, Solubility improvement, Solid dispersion. INTRODUCTION
N
Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). AIDS has been reported to cause more than 25 million deaths worldwide and the World Health Organisation has declared HIV as a pandemic. Among these, half of the patients are women, meaning that women are more likely to get HIV infection compared to men. Due to the unavailability of an effective HIV vaccine, HIV continues to be an important health issue. A vaginal microbicide is considered to be a potential alternative currently being pursued for preventing heterosexual transmission of HIV [1]. Microbicides are antimicrobial products that are applied vaginally and/or in rectum to reduce the transmission of HIV. Early generation microbicides provided only partial protection by forming a physical barrier to the virus or altering the chemistry of vaginal fluids. New generation microbicides contain an antiretroviral product that is specific to HIV [2]. Dapivirine, (Fig. (1)), 4-[[4-[(2,4,6-trimethylphenyl)amino]-2pyrimidinyl]amino] benzonitrile, previously known as TMC 120 is a newly developed anti-HIV drug [1, 3]. It is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which acts by inhibiting the viral enzyme reverse transcriptase preventing transcription of viral genetic material and incorporation in the host’s genome [1, 4-6]. *Address correspondence to this author at the School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; Tel.: + 61 8 8302 1575; Fax: +61 8 8302 2389; E-mail:
[email protected] 1567-2018/13 $58.00+.00
HN N HN N Fig. (1). Chemical structure of Dapivirine.
The oral monotherapy and vaginal microbicidal activity of Dapivirine has been established [1, 5, 7]. However due to its poor aqueous solubility, development of a vaginal microbicide formulation of Dapivirine has been difficult. Hence various pharmaceutical strategies are being designed to improve the solubility and dissolution of Dapivirine in order to prepare a suitable vaginal microbicidal formulation. Solid dispersion is the most promising strategy in improving the dissolution rate of poorly water soluble drugs [8]. It involves the dispersion of the hydrophobic drugs in inert and hydrophilic carriers by solvent, fusion or fusion-solvent methods [9, 10]. The process leads to the conversion of drug crystal lattice into amorphous form, reduction in particle size and hence resulting in better drug wetting ability. Use of suitable carriers also reduces aggregation of the drug particles maintaining improved solubility of the formulation [10]. The type of carrier chosen in a solid dispersion formulation signifi© 2013 Bentham Science Publishers
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cantly affects the dissolution profile of the formulation. Hydrophilic synthetic polymers have been commonly used as carriers for solid dispersion systems [8]. Polyvinylpyrrolidone (PVP k30) and Polyethylene glycols (PEGs) are the most widely employed dissolution rate-enhancing carriers [11]. PVP k30 is a synthetic polymer that is widely used due to its high aqueous solubility, low toxicity and its ability to suppress recrystallization [8, 12]. PEGs are polymers of ethylene glycol having molecular weight in the range of 200 – 300000. PEGs with molecular weight of 1500-20000 are usually employed for the preparation of solid dispersions. These are semi-crystalline polymer known for its relatively low melting point (under 65°C) that makes it an ideal excipient for fusion method of solid dispersion [12, 13]. It has a high aqueous solubility and is also soluble in a range of organic solvents [11].
Gorajana et al.
8000. The resulting mixture was stirred until homogenous and cooled rapidly in an ice bath until the mixture was solidified. The solidified products were scraped, pulverised and sieved through sieve No.80 (180m). The products were then stored in desiccator for future characterization. Table 1.
Composition of Solid Dispersions. Drug: Carrier
Method
Formulation Code
1:1
PM
PM PVP1
1:4
PM
PM PVP4
1:6
PM
PM PVP6
1:1
Solvent-Evaporation
SD PVP1
1:4
Solvent-Evaporation
SD PVP4
1:6
Solvent-Evaporation
SD PVP6
1:1
PM
PM PEG1
1:4
PM
PM PEG4
2.1. Materials
1:6
PM
PM PEG6
Dapivirine was a gift sample from International Partnership for Microbicides, USA. PVP k30 was purchased from Merck, Germany. PEG 8000 was purchased from SigmaAldrich, Malaysia. Milli-Q water was used throughout the research. It was obtained from a CFOF 01205 Milli-Q water purification system (Millipore, USA) with an 18 Mcm resistivity. All others chemicals and reagents used were of analytical grade.
1:1
Fusion
SD PEG1
1:4
Fusion
SD PEG4
1:6
Fusion
SD PEG6
In this article we report the experiments carried out to improve the dissolution rate of Dapivirine by solid dispersion technique using PVP k30 and PEG 8000 as the hydrophilic carriers. The prepared solid dispersions were characterized by powder XRD, FTIR, DSC, SEM, in-vitro dissolution and solubility studies. 2. MATERIALS AND METHODS
Carrier
PVP k30
PVP k30
PEG 8000
PEG 8000
2.2.3. Physical Mixtures PM was prepared by triturating the drug and the polymeric carrier in a mortar pestle for 15 min (Table 1).
2.2. Preparation of Solid Dispersion Systems Solid dispersion formulations were prepared using different weight ratios of drug and carrier as shown in Table 1. The formulations were prepared by two different methods, solvent method and fusion method. Physical mixtures (PM) containing the drug and the carrier were also prepared for comparison. 2.2.1. Solvent Method Solid dispersion with PVP k30 was prepared by solvent method using ethanol as the common solvent. Drug Dapivirine and polymer PVP k30 were dissolved in sufficient quantity of ethanol separately. The two solutions were mixed and sonicated for 15 minutes to obtain a homogenous solution. The solvent was then removed using a hot water bath at 60ºC. Solid residue obtained was kept in an oven at 50°C for 24 hours to remove residual solvent. The resulting products were scrapped, pulverised, sieved through sieve No.80 (180m), filled in screw capped glass bottles and stored in a desiccator until further use. 2.2.2. Fusion Method Solid dispersion was prepared by first melting PEG 8000 in a porcelain dish on a water bath at 65oC. This was then followed by the addition of dapivirine to the molten PEG
2.3. HPLC Analysis of Samples A HPLC system (Shimadzu Prominence 20 with SPD M 20A PDA detector) was used to generate a calibration curve and to quantify drug release. Waters Symmetry RP C-18, 5 μm, 4.6 x 250 mm column was used. The mobile phase consisted of 10 mM ammonium acetate buffer: acetonitrile (ACN) (2:8). The flow rate and column temperature were set at 1.0 mL/min and 30ºC with detection wavelength at 286 nm. Sample chamber temperature was ambient and injection volume was 50 L with run time of 10 minutes. A linear calibration curve for Dapivirine was obtained over the range of 1.0-7.0 g/mL with regression value (R2) of 0.9997. 2.4. Solubility Studies Solubility studies were carried out to determine the solubility of pure drug dapivirine, prepared solid dispersions and PM in ammonium acetate buffer (10 mM; pH 4.5). Solid dispersions and physical mixtures equivalent to 2 mg of the drug were placed in vials with each vial containing 5 mL of solvent. The vials were shaken at 50 rpm at 37oC for 24 h.Each vial was then centrifuged at 10,000 rpm for 10 minutes and the supernatant was filtered through a 0.45 m filter and analysed by HPLC method. The solubility of samples was determined using a previously generated calibration curve.
Solid Dispersion Systems of Dapivirine
2.5. In Vitro Dissolution Test The dissolution test was performed using the dissolution apparatus USP 8-Flask/8-spindle SR8-plus (Hanson Research) with 100 ml of dissolution medium at 37°C using paddle method at a rotation speed of 100 rpm. Pure drug, solid dispersion and physical mixture equivalent to 10 mg of dapivirine were accurately weighed and added into 100 ml of dissolution medium. At appropriate time intervals, 2 ml of medium was withdrawn and filtered through 0.45 m membrane filter. The initial volume was maintained by adding 2ml of fresh dissolution medium. Samples were analysed using HPLC method and the results were computed with Dapivirine standard calibration curve. Studies were performed in triplicates. 2.6. Fourier Transforms Infrared (FTIR) Spectroscopy Bruker Tensor 37 FTIR spectrometer was used in this test to investigate the FTIR spectrum of pure Dapivirine, excipients and the solid dispersion systems. Samples were placed on the small crystal spot in FTIR spectrometer and samples were analysed in a scanning range from 400-4000 cm-1 with resolution at 1 cm-1. 2.7. Differential Scanning Calorimetry (DSC) DSC-60 Shimadzu differential scanning calorimeter was used in this test and the results were analyzed using TA60WS thermal analyzer software. Approximately 5.0 mg of the sample was weighed and placed in an aluminium perforated pan with another empty aluminium pan used as reference. The runs were conducted in a range of 0°C to 300°C at a scanning speed of 10°C/min under dry nitrogen flow (100 ml/min).
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point, rapid solidification, low cost and physiological tolerance [14]. The prepared dispersions were screened based on solubility and dissolution studies. The formulation which showed enhanced dissolution rate was further characterized by FTIR, DSC, powder XRD and SEM studies. 3.1. Solubility Studies The solubility profile of pure drug and solid dispersions are presented in Table 2. Ammonium acetate buffer pH 4.5 was used as the medium in solubility studies because it mimics the pH of the vaginal fluid since vagina is the preferred route of delivery for dapivirine [2]. The pure drug was found to be practically insoluble, but the solubility of the drug was enhanced when carriers were incorporated. However the enhancement of solubility was not high enough from the drug delivery purpose as maintenance of sink condition is important in performing the in-vitro release testing. However for drugs to be administered in vagina, in addition to aqueous component the mucosal tissue also act as a sink and specifically for hydrophobic drugs which can rapidly enter the lipid membrane [15]. Hence it was decided to incorporate the organic solvent into the dissolution media for in-vitro study of formulations as it contains both the aqueous and tissue component in one release media. The percentage of the organic solvent was selected based on the solubility study done previously [16]. Table 2.
Solubility Studies of Solid Dispersions and Physical Mixtures. Formulation Code
Solubility (g/ml)
2.8. X-Ray Powder Diffraction (XRD)
PM PVP1
2.839
X-ray powder diffraction study was performed using D2 Phaser Desktop X-ray Diffractometer from Bruker AXS. The samples were placed in the sample holder and scanned in a range of diffraction angles (2) between 2 to 40°. The radiation was generated by Cu K filter with a wavelength of 1.54178 Å. Diffractograms were run at 40 kV voltages, a 40 mA current and a scanning speed of 0.02°/min.
PM PVP4
4.467
PM PVP6
0.562
SD PVP1
0.823
SD PVP4
1.606
SD PVP6
6.308
Carrier
PM PEG1
0.598
PM PEG4
1.321
PM PEG6
1.902
SD PEG1
0.641
SD PEG4
2.518
SD PEG6
0.574
Pure Dapivirine
0.27
PVP k30
2.9. Scanning Electron Microscopy (SEM) The surface morphology and physical structure of pure drug and the solid dispersion systems were analysed using SEM. Samples of pure drug and solid dispersion formulations were mounted on an aluminium stub using double sided adhesive tape and were then coated with a thin film of platinum at 5-10 mA, 1.1 kV using Polaron SC 7640 sputter coater. The samples were observed under SEM (Philips XL 30S FEG).
3
PEG 8000
-
3. RESULTS AND DISCUSSION Various hydrophilic polymers are available which can be used to prepare solid dispersions. However PVP and PEG are most popular carriers used for the formulation of solid dispersions owing to their low toxicity, availability in range of molecular weights, high aqueous solubility, low melting
3.2. In Vitro Dissolution Test As Dapivirine would be administered as a vaginal microbicide, its dissolution properties should be ideally tested in media closed to physiological environment. Therefore, ammonium acetate buffer (pH 4.5) and methanol (60:40) was
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selected as the in-vitro media for dissolution studies. Initially the solid dispersion and PM formulations which demonstrated increased solubility were tested for their dissolution behaviour. The dissolution study was done for an hour. The results obtained are presented in Fig. (2a); it was observed that the dissolution rate of pure dapivirine was very slow. Solid dispersion formulations showed enhanced dissolution of dapivirine as compared to PM and pure drug. Formulation SD PVP6 exhibited the highest rate of drug dissolution, followed by SD PEG4. The rate of drug release depends upon the rate and extent of penetration of the dissolution media into the drug matrix as well as the relative solubility of the matrix and the drug [17]. Compared to pure Dapivirine, two of the solid dispersion systems showed an improvement in drug dissolution rate. A higher of drug dissolution was expected from the solid dispersion systems due to increased wetting of the drug particles. This in turn is attributed to the reduction of particle size as well as transformation of the crystalline form of the drug into an amorphous form [18]. PM though composed of the same hydrophilic carrier showed intermediate dissolution profile as compared to the solid dispersions suggesting the molecular or colloidal dispersion of drug in polymer matrix in solid dispersion formulation. Formulation SD PEG4, showed a high dissolution rate in first 30 min but eventually the dissolution was decrease after 60 min. The exact reason of this drop is unknown and therefore the dissolution study was repeated for the two solid dispersion formulations and was conducted for 2 h. Fig. (2b) presents the dissolution profile for 2 h and it was observed that similar dissolution profile was obtained for formulation SD PVP6 which almost attains a plateau after 90 min. Formulation SD PEG4 showed almost similar dissolution pattern but less than SD PVP6. The previous drop in the dissolution rate observed with formulation SD PEG4 might be related to processing errors while analysing the samples.
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SD PVP6 solid dispersion system consisted of PVP k30 as the hydrophilic polymer. Use of hydrophilic polymers such as PVP k30 enhances drug dissolution as the polymers absorb water and swell to form a gel-like structure. Due to the swelling of the gel matrix the pores open and the drug particles which are entrapped inside the matrix diffuse out into the solvent [13, 19]. An impressive enhancement of the dissolution was also observed with SD PEG4 formulation, although it exhibited a lower release rates compared to SD PVP6. The less dissolution of the drug may be attributed to the incomplete amorphisation of the drug dapivirine leading to reduced wettability and hence the rate of drug dissolution could have been slower. Previous studies have shown enhanced dissolution profile of poorly soluble drugs like terbinafine[20], valsartan [21] and prednisolone[22] with hydrophilic carriers like PVP k30 and PEG. 3.3. Fourier Transform Infrared (FTIR) Spectroscopy FTIR studies were done to identify the possible chemical interaction between the drug and the hydrophilic carrier. The IR spectrum of selected solid dispersions was compared with the standard spectrum of dapivirine and its respective carrier in Fig. (3). The IR spectrum of dapivirine was characterized by the absorption of N-H group at 3287 cm-1 and C=N group at 2221 cm-1; IR spectrum of PEG 8000 was characterized by the absorption of C-H at 2881 cm-1 and C-O at 1096 cm-1 while the IR spectrum of PVP k30 was characterized by the presence of very broad band at 3400cm-1, due to the absorption of hydrogen-bonded OH group. Other important bands such as, C-H group at 2951 cm-1and C=O group at 1648 cm1 were also present. As shown in Fig. (3), the IR spectrum for SD PEG4 is the summation of the spectrum from both dapivirine and PEG 8000, indicating that N-H, C=N, C-H and C-O groups exist in SD PEG4. Since no new peak was observed in the IR spectrum of SD PEG4, it can be con-
Fig. (2). (a) Dissolution profiles representing cumulative drug release for solid dispersion formulations, physical mixtures and pure dapivirine. Each point represents mean of three simultaneous experiments. (b) Dissolution profiles representing cumulative drug release for two selected solid dispersion formulations. Each point represents mean of three simultaneous experiments.
Solid Dispersion Systems of Dapivirine
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Fig. (3). FTIR spectrum of the pure Dapivirine, PVP k30, PEG 8000 and selected solid dispersion formulations.
cluded that there is no interactions between dapivirine and PEG 8000. Similarly, spectrum of SD PVP6 formulation represents the superposition of both pure Dapivirine and PVP k30 spectra with reduced intensity. The low peak intensities indicated the presence of an amorphous form of Dapivirine in the solid dispersion system SD PVP6 [23]. In addition, Dapivirine compatibility with the excipients that were used in all the solid dispersions system were analysed by HPLC to prove that Dapivirine and the excipients used in the formulations were compatible. 3.4. Differential Scanning Calorimetric (DSC) Fig. (4) shows the DSC thermograms of solid dispersion formulations. The DSC of pure Dapivirine is known to exhibit a melting endotherm at 220oC with transition peak at ~100˚C, whereas PEG shows a single sharp endotherm at 60˚C suggesting the melting of PEG and PVP k30 shows a broad endotherm ranging from 80 to 120oC, due to the presence of residual moisture in PVP k30 [14, 24-26]. DSC thermogram of SD PVP6 showed endothermic peak at ~109oC and 181.91oC. The broad and shallow endothermic peak was due to the water evaporation. The peak corresponding to the melting of the crystalline pure drug was absent in
the solid dispersion formulations which could be due to the presence of amorphous form of the drug. Thermograms showed that drug-polymer interactions were absent and no new peaks were found and also no prominent peak shifting occurred. The DSC thermogram of SD PEG4 showed a sharp endothermic peak at ~60.8o C and a reduced intensity peak at ~99˚C. This might suggest that the dapivirine is not completely present in amorphous form and also exist in crystalline form. These results of DSC studies are further supported by the results from FTIR whereby no drug-polymer interactions were established and also further by XRD analysis. 3.5. X-Ray Powder Diffraction (XRD) Powder XRD was performed to know the physical state (amorphous/ crystalline) of the drug in solid dispersion formulation. In XRD spectra the crystalline state is represented by sharp peaks while such peaks are absent in amorphous form [27]. The spectra of pure Dapivirine and its solid dispersions are shown in Fig. (5). The XRD pattern of pure Dapivirine shows several high-intensity diffraction peaks indicating the crystalline nature of Dapivirine [28]. The prominent peaks of pure Dapivirine were observed at diffraction angles (2) of 10.2˚, 14.2˚, 16.0˚, 19.2˚, 20.7˚, 22.1˚, 23.0˚, 24.0˚, 24.6˚, 25.4˚, 27.1˚ and 28.6˚. However its dispersion in the hydrophilic carrier PVP k30 (SD PVP6) are
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Fig. (4). DSC thermogram of pure Dapivirine and its solid dispersion formulations.
Fig. (5). X-ray diffractogram of pure Dapivirine and its solid dispersion formulations.
completely amorphous as the sharp peaks that corresponds to Dapivirine crystals disappeared in the spectra (Fig. 5) this suggests that polymer PVP k30 inhibited the crystallization
of Dapivirine [29]. On the other hand, the diffraction pattern of solid dispersion SD PEG4 reveals characteristic peak of Dapivirine at 10.2o and 14.2o with reduced intensity, suggesting
Solid Dispersion Systems of Dapivirine
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Fig. (6). SEM photographs of (a) pure Dapivirine, (b) Formulation SD PVP6 and (c) Formulation SD PEG4.
that the drug Dapivirine is still present in the crystalline form in the formulation. The peak at 19.9˚ and 23.3˚ corresponds to the characteristic peak of PEG [29]. However, the crystalline peaks had reduced to a certain extent due to partial amorphisation of drug. A greater degree of amorphisation was observed in the formulation SD PVP6. 3.6. Scanning Electron Microscopy (SEM) The SEM micrographs showed significant differences in the morphology of samples after the formation of solid dispersion systems. Fig. (6(A)) for pure Dapivirine particles showed that the drug particles were present in a crystalline form. The crystals were rectangular in shape with welldefined edges and planes. Solid dispersion SD PVP6 (Fig. (6B)), showed the amorphous form of dapivirine with uniform drug distribution evenly dispersed into the hydrophilic carriers. The formulations SDPEG 4 (Fig. (6C)), showed the presence of both the amorphous and crystalline structures. This explains the reduced dissolution rate of these solid dispersions as compared to formulation SDPVP6, which showed highest dissolution rate among all the solid dispersion formulations of dapivirine.
4. CONCLUSION The study demonstrated that the dissolution rate of Dapivirine can be enhanced through the formulation of solid dispersion systems using water-soluble carriers PVP k30 and PEG 8000. An increment in dissolution rate of all developed solid dispersion formulations was observed due to the transformation of the crystalline state of drug into amorphous state. This finding was supported by XRD, DSC, FTIR and SEM studies. DECLARATION OF INTEREST The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper. ACKNOWLEDGEMENTS Declared none. PATIENT CONSENT Declared none.
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