RESEARCH ARTICLES
`
`
`Solubility enhancement of hydrophobic drugs
`using synergistically interacting cyclodextrins
`and cosolvent
`
`Praveen Chaudhari1,*, Pramodkumar Sharma2, Nilesh Barhate1,
`Parag Kulkarni1 and Chetan Mistry1
`1Padmashree Dr D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411 018, India
`2University Institute of Pharmacy, Bundelkhand University, Jhansi 284 002, India
`
`
`The purpose of the present study was to examine the
`cosolvency and cyclodextrins (CD) addition as a combined
`approach on the solubility of the hydrophobic drug,
`valdecoxib, since solubilization of nonpolar drugs consti-
`tutes one of the most important tasks in liquid orals
`and parenteral formulation design. An attempt has
`been made to improve the solubility of valdecoxib in
`water, using PEG-400, poloxamer-188 and 2 CDs (b -CD
`and Hp-b -CD). The aqueous solubility of valdecoxib
`was 0.01 mg/ml, which was significantly improved by
`addition of PEG-400, CDs and poloxamer-188. In sys-
`tems containing varying amounts of PEG-400 and 1, 2,
`3 and 6% of b -CD or Hp-b -CD in water, theoretical
`solubility was calculated by adding the solubilities in
`the individual system. The theoretical solubility values
`were less compared to the observed solubility values.
`Hp-b -CD showed better solubility than b -CD. Addition
`of poloxamer-188 to the PEG-400/water systems con-
`taining CDs showed significant increase in the solubility
`of valdecoxib; hence synergism was observed. Solubi-
`lity enhancement is due to affinity between the drug
`and interior of the CD host molecules, while the small
`non-polar hydrocarbon region in the cosolvent can
`reduce the ability of the aqueous system to squeeze out
`non-polar solutes. The results show that both cosolvency
`and CD addition are promising approaches for
`enhancing the solubility of valdecoxib.
`
`Keyword: Cosolvency, cyclodextrin, hydrophobic drugs,
`solubility, synergism.
`
`OVER the years, a variety of solubilization techniques
`have been studied and widely used, including pH adjustment,
`cosolvent addition, surfactant addition and cyclodextrin
`(CD) addition. Among these techniques, in this article
`cosolvency and CD addition are applied for non-polar
`solutes. Addition of cosolvent to a formulation is a com-
`monly used method for improving the solubility of the
`drug, because the cosolvent reduces strong water–water
`interactions and thereby reduces the ability of water to
`squeeze out non-polar solutes. Cosolvency was often consi-
`
`*For correspondence. (e-mail: pdchaudhari_21@yahoo.com)
`
`dered at early stages due to its huge solubilization poten-
`tial. Because of their safety, cosolvents are employed in
`approximately 10% of FDA-approved parenteral products1.
`In intravenous (IV) preparation, the 10% ethanol–40%
`propylene glycol combination is most widely employed.
`High concentrations of cosolvent have high viscosity and
`high tonicity, and phlebitis can result from precipitation
`of the solubilized drug upon IV injection. In fact, ethanol
`in concentrations greater than 10% may well produce sig-
`nificant pain2,3.
` CD complexation has been widely used to improve the
`physico-chemical properties of various drug molecules.
`CDs are able to form both inclusion and non-inclusion com-
`plexes. In addition, CDs and their complexes form water-
`soluble aggregates in aqueous solutions. These aggregates
`are able to solubilize lipophillic water-insoluble drugs through
`non-inclusion complexation or micelle-like structures4.
`Such a drug–ligand complex has a rigid structure and a
`definite stoichiometry, usually one-to-one at low concen-
`tration. However, use of CDs in pharmaceutical dosage
`forms is limited by their relatively high cost and due to
`problems of formulation, all principally related to the large
`amount necessary to obtain the desired drug-solubilizing
`effect5. Some CDs are reported to have significant renal
`toxicity6.
` Therefore, it was important to find methods to enhance
`the efficiency of CDs and cosolvents in terms of complexing
`and cosolvency, by making thus possible to considerably
`reduce the dose of both. Recently, the combined use of
`cosolvency and complexation has drawn particular inter-
`est. Loftsson et al.7 reported that addition of polyethylene
`glycol or ethanol in an aqueous solution of CD reduced
`the solubility of ibuprofen. Pitha and Hishino8 reported that
`the solubility of testosterone with hydroxypropyl-b -
`cyclodextrin (Hp-b -CD) is 10,000-fold lower in 80%
`ethanol than in water. The reason behind this was that the
`cosolvent may act by competing with the drug for entry
`into the CD cavity or by reducing solvent polarity. In other
`studies, it was found that the presence of cosolvents increases
`the formation of drug–ligand complex. Zung9 hypothe-
`sized that a series of alcohols have synergistic effect on
`the cosolvency and complexation of pyrene. He also sug-
`
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`gested that the cosolvent could regulate the molecule to
`assist the drug to fit inside the CD cavity.
` Poloxamer-188 is one of the commercial grades of
`poloxamers, which are water-soluble, non-ionic, surface-
`active copolymers. The polyoxyethylene segment of polox-
`amer-188 is relatively hydrophilic, while the polyoxypro-
`pylene segment is relatively hydrophobic. It has been
`used in pharmaceutical formulations, primarily as emulsifying
`and solubilizing agents10. It has the ability to form a clear
`solution or gel in aqueous media, thus solubilizing many
`water-insoluble compounds by the formation of micelles11.
`Thus, poloxamer-188 has been selected for the study of
`improvement in the solubility and synergistic effect on
`the hydrophobic moiety.
` Both cosolvency and complexation have been well studied.
`It is of interest to explore the mechanisms of the combined
`effect of the two techniques on non-polar drug solubiliza-
`tion and to explore the dynamics among the solute, cosol-
`vent and CD. The main objective of our study was to
`explain the combined effect of cosolvency and cyclodex-
`trin addition on non-polar drug solubilization.
`
`In the present study, valdecoxib (Scheme 1) was sele-
`cted as a model drug and PEG-400 was used as cosolvent
`for improving the aqueous solubility of hydrophobic drugs.
`Harada et al.12 reported that PEGs form complexes with
`a -CD and g -CD, but not with b -CD. In the present study
`therefore, b -CD and Hp-b -CD were chosen to examine
`the effect of CDs and PEG-400 on the solubility of
`valdecoxib. Solubilization of valdecoxib was also exam-
`ined using poloxamer-188 on the synergism of PEG and
`CD.
`
`Materials and methods
`
`Valdecoxib was obtained as a gift sample from Alembic
`Ltd, Baroda, India. b -CD and Hp-b -CD were obtained
`from Lupin Research Centre, Pune, India. PEG-400 was
`obtained from Qualigen, India and poloxamer-188 was
`obtained as a gift sample from BASF India Ltd, Mumbai,
`India.
` All other chemicals were of analytical reagent grade,
`and freshly prepared distilled water was used throughout
`the study.
`
`
`
`Scheme 1. Valdecoxib.
`
`
`
`RESEARCH ARTICLES
`
`Solubility studies
`
`Solubility measurements were determined in various sol-
`vents, namely water, PEG-400, aqueous solutions of
`poloxamer-188, and 1, 2, 3 and 6% aqueous solution of
`b -CD and Hp-b -CD. Excess amounts of valdecoxib were
`weighed into glass vials containing 10 ml solvents. The
`samples were shaken at 25 –
` 2(cid:176) C for 24 h and passed
`through a 0.45 m m filter. Next 1 ml of filtered solution
`was diluted to 10 ml using ethanol (which was previously
`used to develop the calibration curve). The concentrations
`of dissolved valdecoxib were analysed spectrophotometrically
`(UV-1700, Shimadzu) at a wavelength of 246.5 nm. PEG-
`400–water and PEG-400–water–poloxamer-188 cosolvent
`systems were prepared by weight. The solution containing
`increasing amount of PEG-400 (1–90%) in PEG-400–
`water cosolvent system was prepared and solubilization
`capacity of the cosolvent system was investigated. In another
`set of experiments, the solubility of valdecoxib was de-
`termined in 50% PEG–water system containing 1, 2, 3
`and 6% of aqueous solution of b -CD and Hp-b -CD indi-
`vidually, as well as in the presence of poloxamer-188 (0.5
`and 1.0%).
`
`UV method for analysis
`
`Valdecoxib is freely soluble in ethanol. Hence ethanol was
`used as a solvent to develop the calibration curve of val-
`decoxib using the UV method. The concentration range
`of 2–16 m g/ml was found to obey Beer–Lambert’s law.
`The working curve equation for valdecoxib was
`
` Y = 0.0595X + 0.0125,
`
`with correlation coefficient r2 = 0.999.
` Once the equilibrium solubility was achieved after
`shaking the drug with the PEG-400–water system for 24 h,
`the solution was filtered and 1 ml of it was diluted to 10 ml
`with ethanol (which was previously used to develop the
`calibration curve). Absorbances were measured at 246.5 nm
`using a UV spectrophotometer.
` The UV spectrometer was previously calibrated accord-
`ing to the method mentioned in Indian Pharmacopoeia (I.P.)
`1996, i.e. control on absorbances test, in which absorb-
`ance of potassium dichromate solution was checked at the
`wavelengths indicated in I.P. 1996. The A (1%, 1 cm) for
`each wavelength was measured and found in the permitted
`limits according to I.P. 1996.
`
`Results and discussion
`
`The solubility enhancement of valdecoxib by use of PEG
`4000 (ref. 13) and CD14 has been extensively studied. In
`the present investigation, solubility enhancement caused
`by complexation with different concentrations in b -CD
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`the solubility in PEG-400–water + 2% b -CD system was
`much less compared to PEG-400–water + 2% Hp-b -CD
`system. Solubility values achieved in the PEG-400–water
`system containing 3 and 6% of both b -CD and Hp-b -CD
`are given in Tables 4 and 5 respectively. Increase in solu-
`bility of valdecoxib was observed in 3 and 6% of Hp-b -
`CD than in 3 and 6% of b -CD. Improvement in solubility
`due to synergism was observed in all systems. Synergism
`was higher in case of Hp-b -CD than in b -CD. Overall,
`PEG-400, b -CD and Hp-b -CD showed a synergistic effect,
`described by an increase in solubility produced by cosol-
`vent as well as increase in solubility produced by the
`CDs, in improving valdecoxib solubility in water.
` Hydroxypropyl substitution in b -CD may have resulted
`in higher binding constants than those observed with b -
`CD apparently due to the extension of the hydrophobic
`cavity16. Hence the solubility of valdecoxib may be higher
`in Hp-b -CD than in b -CD. The percentage increase in
`solubility of valdecoxib was found to be higher at 10%
`PEG-400 in the PEG-400–water system in all cases. The
`percentage increase in solubility increases with the addi-
`tion of b -CD, i.e. 6 > 3 > 2 > 1%. Similar results were
`obtained in case of Hp-b -CD.
` Results from the present study shows that poloxamer-
`188 has significant solubilization effect on valdecoxib at
`25 –
` 2°C (Figure 1 a–d). Solubility of valdecoxib increased
`as the concentration of poloxamer-188 in the PEG–CDs
`solution was increased from 0.5 to 1%. Poloxamer-188 may
`enhance the solubility of valdecoxib either by micellar
`solubilization or reducing the activity coefficient of the
`drug by reducing the hydrophobic interaction or both proc-
`esses. In addition, improvement in the wetting of the hydro-
`phobic valdecoxib crystals may occur, which is needed
`for solubilization, contributing to increase in the synergistic
`effect. At low concentrations, the poloxamer monomers
`are thought to form monomolecular micelles by a change
`in configuration in solution. At higher concentration, these
`monomolecular micelles associate to form aggregates of
`varying sizes, which have the ability to solubilize drugs
`and to increase the stability of solubilizing agents.
` The binding affinity between the CD molecule and the
`inclusion compound is influenced by the molecular prop-
`erties of the guest molecule as well as the CD used. Its in-
`ternal cavity has the ability to incorporate hydrophobic
`aromatic guest molecules in aqueous solution, provided
`that the host internal cavity and the entry point of the
`guest molecule are suitable for complexation. Steric as
`well as electrostatic parameters influence inclusion com-
`plexation, as the molecular surface of the guest molecule
`should fit as accurately as possible into the interior of the
`CD17. Moreover, electrostatic potential and hydrophobicity
`affect the binding affinity to a great extent. A variety of
`factors, such as van der Waals, hydrogen bonding and
`hydrophobic forces, play an important role in forming a
`stable complex18. The flexibility of the host molecule is
`an additional parameter which is responsible for the
`
`RESEARCH ARTICLES
`
`compared to that of Hp-b -CD was determined under the
`influence of PEG-400 as cosolvent. The solubility en-
`hancement of valdecoxib at 25(cid:176) C in the presence of PEG-
`400, poloxamer-188 and with diffferent concentrations of
`b -CD and Hp-b -CD is given in Table 1. The solubility of
`valdecoxib increases with increasing amounts of both
`CDs, due to the increasing concentration of valdecoxib in
`complexed form. The solubility increased in both systems
`with further addition of CDs, but it was found that Hp-b -
`CD dissolves valdecoxib slightly better.
` The solubility of low-soluble compounds and their as-
`sociation equilibria with CD were strongly influenced by
`the cosolvent. Therefore, addition of cosolvents only changes
`the solubilites of compounds to higher extent. Seedher
`and Bhatia15 reported that improvement in solubility using
`cosolvent may be due to physico-chemical properties of
`the solvent, such as polarity, intermolecular interactions,
`and the ability of the solvent to form a hydrogen bond
`with the drug molecules. In a 50% PEG-400–water system,
`solubility of valdecoxib decreases. The theoretical and
`observed solubility values of valdecoxib in the PEG-400–
`water system containing 1% b -CD and 1% Hp-b -CD at
`25 –
`2(cid:176) C are listed in Table 2. In solutions containing Hp-
`
`b -CD, at lower PEG-400 concentrations (less than 50%),
`the observed solubility was significantly greater than the
`expected solubility. For example, the theoretical value in
`30% PEG-400–water system containing 1% Hp-b -CD was
`1.60 mg/ml. The observed solubility of valdecoxib in the
`same system was 2.57 mg/ml, showing approximately a
`60.62% increase in comparison to the theoretical value.
`The influence of PEG-400 on valdecoxib solubility in 2%
`b -CD and 2% Hp-b -CD is given in Table 3. While the
`PEG–CD system shows profound increase in solubility,
`
`Table 1. Solubility of valdecoxib in selected vehicles at 25 –
`
` 2(cid:176) C
`
`
`
`Vehicle
`
`
`
`Solubility of valdecoxib (mg/ml)*
`36.65 –
` 3.07 –
` 2.59 –
` 1.76 –
` 1.46 –
` 1.14 –
` 1.11 –
`0.92 –
` 1.99 –
` 3.45 –
` 0.1 –
` 0.12 –
` 0.13 –
`0.184 –
`0.119 –
`0.158 –
`0.226 –
`0.383 –
` 0.01 –
`
` 0.05
` 0.07
` 0.06
` 0.04
` 0.06
` 0.02
` 0.03
` 0.2
` 0.03
` 0.05
` 0.02
` 0.04
` 0.05
` 0.03
` 0.08
` 0.06
` 0.02
` 0.05
` 0.0004
`
`PEG-400
`PEG-400/water (90 : 10)*
`PEG-400/water (70 : 30)*
`PEG-400/water (50 : 50)*
`PEG-400/water (30 : 70)*
`PEG-400/water (10 : 90)*
`PEG-400/water (05 : 95)*
`PEG-400/water (01 : 99)*
`0.5% Poloxamer-188
`1% Poloxamer-188
`1% b -CD
`2% b -CD
`3% b -CD
`6% b -CD
`1% Hp-b -CD
`2% Hp-b -CD
`3% Hp-b -CD
`6% Hp-b -CD
`Water
`Expressed as mean –
` SD (n = 3).
`*Solubility measurement in 50% PEG-400–water system.
`
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`Table 2. Solubility of valdecoxib in PEG-400–water systems with 1% b -CD and 1% Hp-b -CD at 25 –
`
` 2(cid:176) C
`
`
`
`
`
`Solubility of valdecoxib (mg/ml)
`
`Percentage of PEG-400
`in PEG-400–water system
`
`Theoretical value*
`with 1% b -CD
`
`Observed value
`with 1% b -CD
`
`Theoretical value*
`with 1% Hp-b -CD
`
`Observed value
`with 1% Hp-b -CD
`
`
`
`90
`70
`50
`30
`10
` 5
` 1
`
`3.17
`2.69
`1.86
`1.59
`1.24
`1.21
`1.02
`
`3.29 (3.78%)
`2.90 (7.8%)
`2.35 (26.34%)
`1.98 (24.52%)
`1.57 (26.62%)
`1.33 (9.91%)
`1.10 (7.84%)
`
`3.19
`2.70
`1.88
`1.60
`1.30
`1.24
`1.05
`
`3.29 (3.13%)
`3.01 (11.48%)
`2.94 (56.38%)
`2.57 (60.62%)
`2.08 (60.00%)
`1.72 (38.70%)
`1.31 (24.76%)
`
`*For Tables 2–5, theoretical solubility value is the summation of solubility of valdecoxib in 1, 2, 3 and 6% aqueous solu-
`tion respectively as well as in a PEG-400–water system.
`Values in brackets indicate percentage increase in solubility, which is calculated using the following equation.
`Per cent increase in solubility = (Observed solubility – Theoretical solubility) ·
` 100/Theoretical solubility.
`
`Table 3. Solubility of valdecoxib in PEG-400–water systems with 2% b -CD and 2% Hp-b -CD at 25 –
`
` 2(cid:176) C
`
`
`
`
`
`Solubility of valdecoxib (mg/ml)
`
`Percentage of PEG-400
`in PEG-400–water system
`
`Theoretical value*
`with 2% b -CD
`
`Observed value
`with 2% b -CD
`
`Theoretical value*
`with 2% Hp-b -CD
`
`Observed value
`with 2% Hp-b -CD
`
`
`
`90
`70
`50
`30
`10
` 5
` 1
`
`
`
`3.19
`2.70
`1.88
`1.59
`1.29
`1.23
`1.05
`
`3.56 (11.59%)
`3.09 (14.44%)
`2.67 (42.02%)
`2.31 (45.28%)
`1.95 (51.16%)
`1.78 (44.71%)
`1.21 (15.23%)
`
`3.22
`2.74
`1.92
`1.64
`1.33
`1.28
`1.09
`
`4.20 (30.43%)
`4.01 (46.35%)
`3.86 (101.04%)
`3.44 (109.7%)
`3.10 (133.0%)
`2.72 (112.5%)
`2.21 (102.7%)
`
`Table 4. Solubility of valdecoxib in PEG-400–water systems with 3% b -CD and 3% Hp-b -CD at 25 –
`
` 2(cid:176) C
`
`
`
`Solubility of valdecoxib (mg/ml)
`
`Percentage of PEG-400
`in PEG-400–water system
`
`Theoretical value*
`with 3% b -CD
`
`Observed value
`with 3% b -CD
`
`Theoretical value*
`with 3% Hp-b -CD
`
`Observed value
`with 3% Hp-b -CD
`
`
`
`90
`70
`50
`30
`10
` 5
` 1
`
`3.20
`2.72
`1.91
`1.61
`1.31
`1.25
`1.06
`
`3.78 (18.12%)
`3.37 (23.89%)
`3.04 (59.16%)
`2.82 (75.15%)
`2.43 (85.49%)
`1.90 (52.0%)
`1.41 (33.01%)
`
`3.27
`2.81
`1.98
`1.71
`1.40
`1.35
`1.16
`
`6.88 (110.3%)
`5.91 (110.32%)
`5.37 (171.2%)
`4.89 (185.9%)
`4.02 (200.0%)
`3.76 (178.5%)
`2.99 (157.7%)
`
`
`
`
`
`
`
`
`
`geometry and consequently for the stability of the com-
`plex. The type, length and degree of substitution also
`affect the solubilization effect of the CDs.
` Water as a solvent has some unique properties: large
`surface tension (71.8 dynes/cm), a high level of hydrogen
`bonding and a sizable dielectric constant (80 at 20(cid:176) C). The
`structure of PEG-400 is H–(O–CH2–CH2)n–OH, where n
`is approximately 8 to 9. Hydrogen bonding makes this
`peculiar structure of PEG miscible with water. Hydrogen
`bonding between water molecules is broken with the help
`of hydrophobic hydrocarbon regions of insoluble drugs,
`thus reducing intermolecular interactions19. Also it can be
`
`stated that PEG may assist to reduce the dipole moment
`of water and allow hydrophobic compounds to fit in.
`
`In the early 1990s, the solubilization capacity of CDs
`was believed to be reduced by the use of cosolvent. The
`solubility of testosterone with Hp-b -CD was 10,000-fold
`lower in 80% ethanol than in water8. However, in recent
`years polymers have been reported to improve the solubili-
`zation capacity of CDs. Li et al.20 developed a mathe-
`matical model to explain the decrease in drug solubility
`produced by low cosolvent concentrations as well as the
`increase in solubility produced by high cosolvent concen-
`trations that are observed at all CD concentrations. The
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`
`Table 5. Solubility of valdecoxib in PEG-400–water systems with 6% b -CD and 6% Hp-b -CD at 25 –
`
` 2(cid:176) C
`
`
`
`
`
`Solubility of valdecoxib (mg/ml)
`
`Percentage of PEG-400
`in PEG-400–water system
`
`Theoretical value*
`with 6% b -CD
`
`Observed value
`with 6% b -CD
`
`Theoretical value*
`with 6% Hp-b -CD
`
`Observed value
`with 6% Hp-b -CD
`
`
`
`90
`70
`50
`30
`10
` 5
` 1
`
`3.27
`2.75
`1.96
`1.67
`1.37
`1.31
`1.12
`
`4.02 (22.93%)
`3.81 (38.54%)
`3.39 (72.95%)
`2.99 (79.04%)
`2.72 (98.54%)
`2.36 (80.15%)
`1.99 (77.67%)
`
`3.45
`2.97
`2.15
`1.87
`1.56
`1.51
`1.32
`
`11.59 (235.9%)
`10.87 (265.9%)
`8.80 (309.3%)
`8.35 (346.5%)
`7.50 (380.7%)
`5.95 (294.03%)
`3.86 (192.4%)
`
`Figure 1. Effect of 0.5% poloxamer-188 and b -CDs (a); 0.5% poloxamer-188 and Hp-b -CDs (b); 1% poloxamer-
`188 and b -CDs (c), and 1% poloxamer-188 and Hp-b -CDs (d) on solubility of valdecoxib.
`
`
`
`
`
`
`
`
`
`results obtained by us were similar to those reported by Li
`et al.20. Faucci and Mura21 studied synergism between
`CD and water-soluble polymers on naproxen solubility. The
`water-soluble polymers increased the complexation effi-
`cacy of CDs toward naproxen. Viernstein et al.22 reported
`the influence of ethanol as cosolvent on the solubility en-
`hancement of triflumizole by complexation with b -CD
`and with dimethyl-b -CD. They reported the linear de-
`pendence of non-polar solute solubility upon CD concen-
`tration that is observed at all ethanol concentrations.
`Liberation of a solute molecule, creation of a hole in the sol-
`vent, and accommodation of the solute molecule in the
`
`solvent cavity are the most fundamental models involved
`in the solubilization of a solute in a solvent. The intermo-
`lecular forces of attraction in dissolving a solute should be
`reduced in order to improve the solubility of the drug23.
`Four types of interactions, namely solute–solvent, ion–
`dipole, dipole–dipole and hydrogen bonding–hydrophobic
`moiety have been reported. If the system consists of
`polymers, conformation of the polymer chains also plays
`a role in solute–solvent interaction. In the present study,
`the system examines the potential of b -CD, Hp-b -CD,
`PEG-400 and poloxamer-188 as solubilizing agents for
`valdecoxib. The synergistic effect of CD and PEG-400 in
`
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`9. Zung, J. B., Influence of alcohol addition on the g -CD : pyrene
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`Received 5 July 2006; revised accepted 22 January 2007
`
`
`the present study could be attributed to additional breaking
`of hydrogen bonds in the structure of water and a decrease
`in the dipole moment.
`
`Conclusion
`
`Our results suggest that the increase in valdecoxib solu-
`bility was due to synergistic effect in the presence of CDs
`and PEG-400, as well as increase in CD complexation ef-
`ficiency. Addition of PEG-400, poloxamer-188 and CDs
`increased
`the solubility of
`the model drug from
`0.01 mg/ml in distilled water. However, addition of polox-
`amer-188 made the system more complex and hampered
`the synergistic effect at higher concentrations. The pre-
`sent study describes the increase in solubility produced
`by cosolvents as well as the increase in solubility pro-
`duced at all CD concentrations. Thus it provides the dynamics
`of the combined cosolvent–CD technique in solubiliza-
`tion of non-polar drugs.
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