Physical Form Of Active Pharmaceutical Ingredient Biology Essay

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Physical form of active pharmaceutical ingredient plays an important role in its formulation development and biopharmaceutical performance. It is estimated that more than 40% of APIs being identified through combinatorial screening programs are poorly soluble in water, which is a critical determinant for dissolution and oral bioavailability (Lipinski 2001; 2002). Pharmaceutical cocrystals have been emerged as an alternative for APIs, presenting enhanced dissolution and bioavailability. Cocrystals represent a class of crystalline solids which consist of two or more molecular species usually held together by non-covalent bonds (Etter and Frankenbach, 1989; Caira et al., 1995; Aakeroy, 1997; Rodriguez-Spong et al., 2004; Sun and Hou, 2008). Taking into account the advantages and intellectual property potential of pharmaceutical cocrystal, more and more APIs were screened in last two decades for their cocrystal forming ability using different cocrystallization techniques (Shan et al., 2002; Fleischman et al., 2003; Trask et al., 2005; McNamara et al., 2006; Zhang et al., 2007; 2009, Berry et al., 2008, Lu et al., 2008, Friscic and Jones, 2009; Sheikh et al).

Very recently, ultrasound has been used for cocrystal formation from suspension, solution and melts (Childs et al., 2005; Bucar and MacGillivray 2007; Friscic et al., 2009 and Aher et al 2010). Use of ultrasound was found to be advantageous in obtaining pure cocrystal from a solution of a non-congruently soluble cocrystal component pair where convetional solvent cooling techniques failed. Ultrasound assisted solution cocrystallization (USSC) was reported for a non-congruently soluble pair of caffeine and maleic acid to obtain caffeine/maleic acid 2:1 cocrystal (Aher et al 2010), where cocrystal formation was explained using solubility and rate of attainment of supersaturation of cocrystal components due to sonication. For such a system, molar content of more soluble component (maleic acid) in a solution was found to be more than less soluble component (caffeine).

In present research, USSC has been used to obtain carbamazepine/saccharin 1:1 cocrystal from a solution of cocrystal components. Carbamazepine/saccharin 1:1 cocrystal has been reported previously by solvent evaporation, conventional solvent cooling and grinding techniques (Fleischman et al 2003; Jayasankar et al 2006; Hikey at al 2007) and offered advantages over carbamazepine with respect of polymorphism, physical and chemical stability, and improved oral bioavailability. Carbamazepine and saccharin represent a congruently soluble pair in a reported solvent system of methanol/ethanol (37.5:62.5 v/v) (Hikey et al., 2007) (solubility at 25 ± 2 °C of carbamazepine: 434 ± 28 mg/ml and saccharin: 493 ± 21 mg/ml, approximately). For such a congruently soluble system, the molar ratio of cocrystal forming components in solution in USSC has been expected to be same as their stoichiometric ratio in cocrystal.

In the present context, we have prepared carbamazepine/saccharin 1:1 cocrystal by USSC and solvent cooling techniques. Carbamazepine/saccharin 1:1 cocrystal obtained by solvent cooling crystallization technique was considered as reference for the product obtained by USSC. The potential cocrystal products were characterized using PXRD, DSC and Raman spectroscopy. The effect of saturation level and sonication parameters (sonication amplitude and sonication duration) on cocrystal formation was also studied in USSC. Ultrasound application in crystallization phenomenon has shown to alter the morphology and crystal habit (Amara et al 2001, Guo et al 2005). Therefore, product of USSC has been also compared with solvent cooling product to understand the effect of ultrasound on cocrystal particle characteristics. Similar solvent system has been used in these two techniques to obtain cocrystal, as change in solvent system in crystallization process has also shown dramatic effect on crystal habit and morphology (Nokhodchi et al 2003, Chen et al 2008). Particle morphology and surface characteristics of cocrystal obtained by these two techniques were compared using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). AFM is an ideal technique for quantitatively measuring the surface characteristics at nanometer scale and visualizing the surface properties of different material surfaces (Simpson et al 1998, Li et al 2000 and Jones et al 2008). In present study, AFM imaging has been carried out to observe surface roughness difference between cocrystal surfaces obtained by two different techniques. Root-mean-square roughness (Rq) and arithmentic roughness (Ra) have been used for surface roughness measurement using contact mode AFM. Application of ultrasound has shown degradation of product due to oxidative stress as free radicals are generated during sonication (). Therefore, cocrystal product obtained by USSC has been analyzed by HPLC for detection of any degradation impurity. Improvement in compaction property of carbamazepine due to cocrystal formation is also discussed.

2 Materials and methods

2.1 Materials

Carbamazepine (batch number CBZ/0510240) was a generous gift sample from Sun Pharmaceuticals Pvt. Ltd. (Mumbai, India). Saccharin was procured from Loba chemie pvt ltd. (Mumbai, India). Other solvents and chemicals were purchased from Merk India (Mumbai, India) and used as received.

2.2 Methods

2.2.1 Preparation of carbamazepine/saccharin 1:1 cocrystal

A] Solvent cooling

The co-crystal was prepared using previously reported solvent cooling technique (Hickey et al 2007) and considered as a reference for the product of USSC. Cocrystallization was performed in 500 ml jacketed crystallization vessel having constant speed stirrer with propeller having three-blades (1-3 cm) (Eurostar power control-visc, IKA Labortecnik, Germany) with attached digital thermometer and a reflux column. Temperature of the solution was maintained by a circulating water bath (Haake Phoenix C25P, Germany). Anhydrous carbamazepine (7.5 gm, 0.03177 mol) and anhydrous saccharin (5.81 gm, 0.03177 mol) were added to crystallization vessel. The solids were dissolved in 100 ml solvent system (ethanol: methanol, 62.5: 37.5 v/v) by heating it at 70 °C for 1 h under reflux. Solution temperature was decreased in 5 °C increments under stirring condition and equilibrium was achieved at 25 °C. The product was isolated using Buchner funnel and rinsed with cold ethanol. The collected product was dried in air and characterized to confirm the identity of the carbamazepine/saccharin 1:1 cocrystal.

B] Ultrasound assisted solution cocrystallization (USSC)

The equipment used was consisted of a probe and high intensity ultrasonic processor/sonifier (Sonics and Materials Inc., Vibra Cell, Model VCX 500, Connecticut, USA) with temperature controller microprocessor. A high intensity solid probe (tip diameter 13mm) was immersed (tip approximately 2 cm above from the bottom of sonoreactor vessel) in the processing liquid. The device was operated at a fixed wavelength of 20 kHz and capable of inducing a maximum power output of 500W.

Anhydrous carbamazepine (7.5 gm, 0.03177 mol) and anhydrous saccharin (5.81 gm, 0.03177 mol) were dissolved in 100 ml of solvent system (ethanol: methanol; 62.5: 37.5 v/v) at 70 °C. The solution was transferred to 500 ml jacketed glass sonoreactor. The clear solution was subjected to several ultrasound pulses in a jacketed glass sonoreactor vessel using high intensity ultrasound probe (an ultrasonic pulse of 10 seconds with relaxation time of 2 second was employed) when the temperature of solution was in the range of 55-60 °C. During sonication, cold water (15 ± 2 °C) was circulated through glass sonoreactor jacket using circulating water bath. Sonication was terminated when solution became turbid, temperature was decreased to 25 °C and equilibrium was achieved at this temperature. The product was isolated using Buchner funnel and rinsed with cold ethanol. The collected product was dried in air and characterized to confirm the identity of the co-crystals. Different sets of experiments were carried out according to Table 1, to study the effect of sonication amplitude, sonication time and cocrystal component saturation level in solution on co-crystal formation.

Effect of saturation level on cocrystal formation was studied by sonicating saturated equimolar solution of carbamazepine and saccharin (table 1, batch F). Saturated solution was obtained by dissolving anhydrous carbamazepine (3.86 gm; 0.0163 mol) and anhydrous saccharin (2.98 gm; 0.0163 mol) in 100 ml of solvent system at 25 °C by stirred for 30 min at 20 rpm and filtered. Filtrated solution was further subjected to sonication as mentioned above. Temperature was maintained at 25 °C throughout the sonication period (water (25 ± 2 °C) was circulated through glass sonoreactor jacket to avoid excess heating to liquid). The product was dried in air and characterized to confirm the identity of the co-crystals. All product samples were stored in desiccated environment for further study.

2.2.2 Physical Characterization of cocrystals

X-ray Powder Diffraction (PXRD)

Cocrystal formation was ensured using PXRD patterns. PXRD patterns of different samples were recorded using a Bruker D8 Diffractometer (wavelength of X-rays 0.154 nm Cu source, voltage 40 kV, and filament emission 40 mA). Samples were placed into a sample specimen holder and scanned from 2 to 30° 2θ with step size of 0.02° 2θ, step time of 2 seconds and sample rotation of 30 rpm. The data were analyzed using DIFFRACplus EVA (Version 11.0) software.

Raman spectroscopy

Raman microscope and Renishaw InVia Reflex benchtop spectrometer coupled with 785nm stabilized diode (Renishaw Plc., UK) were used for raman spectra measurement. A laser spot of diameter 2µm was obtained at the specimen using a 50X objective lens. Spectra were recorded over the region 1800 to 100 cm-1 and 10 scans were collected for each sample. Data analysis was performed using Galactic Grams AI 8.0 spectroscopy software (Thermo Electron Corporation).

High performance liquid chromatography (HPLC)

The HPLC system specifications were as follows: pump, PU-1580 (JASCO, Japan); injector, auto sampler (AS-1555; JASCO); column, RP C18, 250 X 4.6 mm, 5 µ (Thermo Electron Corporation, USA); detector, UV/Visible (UV-1575; JASCO). Data acquisition and analysis was carried out using Borwin/HSS 2000 software (LG 1580-04; JASCO). The chromatographic conditions were as follows: mobile phase acetonitrile: methanol: water (15:35:40, v/v/v); flow rate, 1 ml/min. The mobile phase was filtered through membrane filter 0.45 µm and degassed before use. The elution was monitored at 270 nm. The injection volume was 20 µL. The peak area of carbamazepine and saccharin were used for quantification of samples. Calibration curve for carbamazepine and saccharin were performed in the range of 5-50 μg/mL in mobile phase.

Scanning electron microscopy (SEM)

SEM was used to visualize surface characteristics and particle size comparison of different products. Samples were mounted on the aluminum stubs and coated with a thin gold-palladium layer by auto fine coater unit (Jeol, JFC, Tokya, Japan). The surface topography was analyzed with a Jeol scanning electron microscope (JSM-6360A, Tokya, Japan) operated at an acceleration voltage of 10 kV.

AFM:

AFM measurements were performed using a commercial atomic force microscope (DimensionTM 3100 Atomic Force Microscope with Nanoscope IV Scanning Probe Microscope Controller, Digital Instruments, Vecco Instruments Ltd, UK). All images were acquired in air using contact mode AFM over different scanning area. Silicon nitride cantilevers (V-shaped) with integrated pyramidal tips and normal spring constant of k = 0.01-0.064N/m) were used. Crystals/small crystal agglomerates were removed from the desiccator and immediately fixed to stainless steel AFM sample discs using superglue. Scanning was carried out in air within 3hrs of removing the sample from desiccators under normal conditions of room temperature (25 -C), atmospheric pressure and approximately 40% relative humidity. During scanning, set point voltage was continually adjusted to the lowest value for which tip-surface contact could be maintained, so as to minimize the force applied and reduced damage to the scanning surface. The scan rate of 2 Hz was employed; height and deflection data were collected simultaneously. The scans were analysed using NanoscopeTM software version 6.11. Surface roughness was measured from different scan sizes as roughness parameters depend on examination scale range (Feninant et al., 2001)

2.2.3 Compaction study

Compaction of cocrystal product obtained by solvent cooling and USSC was carried out using Caleva Compaction Study Press (Caleva Process Solutions Ltd, Dorset, England) coupled with Compaction Study Press Powder v.10.1 software. Flat round punch tooling of 10 mm were used which was lubricated each time with magnesium stearate prior to compaction. Die cavity was filled with either of the powder (carbamazepine/solvent cooling cocrystal product/USSC cocrystal product) weighting 200 ± 2 mg and 5 compacts were prepared each at 1000N, 5000N, 10000N and 20000N force. An attack rate of 100mm/sec and dual time 0.1 was employed during compaction. Thickness and crushing strength and of a compact was measured immediately after compact preparation using Thickness Gauge Instrument (digital type) (Mitutoyo Corporation, Kanagawa, Japan) and Schleeuniger - 4M hardness tester (Copley Instruments, Nottingham, UK), respectively. Tablets were also analyzed visually for surface smoothness.

2.2.4 Solubility study and In vitro drug release

Saturation solubility measurements in water and solvent system (ethanol: methanol; 62.5: 37.5 v/v) used in co-crystallization techniques of pure carbamazepine and cocrystal obtained by USSC and solvent cooling techniques were carried out by adding known excess amount of solid to 20 ml water. Samples were stirred at 20 rpm in a water bath (37 ± 0.5 °C) for 24 h. Samples were then filtered through 0.45 µm membrane filter, diluted with water and then analyzed by HPLC.

The dissolution studies were performed using USP 24 type II dissolution test apparatus (TDT-06P, Electrolab, India). Simulated gastric fluid (SGF) was prepared with 2 g/L NaCl and 1 g/L Triton X-100, and acidified to pH 2 with HCl. Bath temperature was maintained at 37 ± 0.5 °C and stirred at 100 rpm. Samples were collected at 5, 10, 15, 20, 30, 44, 60, 90, 120, 150 and 180 min and replaced with a fresh dissolution medium maintained at same temperature. Samples were centrifuged, filtered through 0.45 μm membrane filter and suitable diluted. Concentration of carbamazepine was determined spectrophotometrically (Jasco V-630, Jasco Corporation, Japan) at 320 nm to eliminate effect of saccharin, which does not absorb significantly at this wavelength. Data was analyzed by PCP-Disso software (V3, Poona College of Pharmacy, Pune, India). To nullify the effect of particle size on dissolution batches of pure carbamzepine and cocrystal obtained by USSC and solvent cooling techniques were passed via metal mesh sieves and fraction of particle size below 50 µm were taken for drug release study. Three capsules of size 0 for carbamazepine and cocrystal products obtained by USSC and solvent cooling were prepared with product equivalent to 200 mg of carbamazepine, and each capsule was placed in dissolution vessel containing 900 ml of SGF.

Statistical analysis of the effects of different batches (Pure carbamazepine, and cocrystal obtained by USSC and solvent cooling techniques) on saturation solubility of drug or percent drug release for each batch at each time point was performed using Kruskal-Wallis test and individual differences between various samples were examined using Dunn's post hoc test. A significance level of P < 0.05 was considered as significant.

3 Results and discussion:

Carbamazepine/saccharin 1:1 co-crystal product obtained by solvent cooling were rectangular, colorless when observed under optical microscope which is in agreement with previous report (Hickey et al 2007) and the product yield was 76 %, approximately. Cocrystal formation was observed within temperature range of 50 - 55 °C. During preliminary study of USSC, positive effect of sonication was seen on crystallization indicating its effect on the induction of nucleation. During this process effect of concentrations of co-crystal components, sonication amplitude and sonication time on co-crystal formation was studied and results are shown in Table 1. The product yield for all batches carried out by USSC varied from 82 to 88% indicating good recovery. Particles of USSC products were also colorless and rectangular as that of solvent cooling product (Figure 1) when observed under optical microscope, but were of very fine size than that of product particles obtained by solvent cooling. In USSC, sonication must have favored generation of large number of primary nuclei in solution over crystal growth, which resulted in production of fine particles. Whereas, in solvent cooling, crystal growth was favored over primary nucleation resulting in larger particles than USSC

3.1 Physical Characterization of co-crystals

XRPD patterns of pure carbamazepine, SA, and cocrysal obtained by solvent cooling and USSC (batch A to F) are shown in figure 2. Diffractogram of pure carbamazepine showed peaks at 2θ = 13.1, 15.2, 15.8, 27.5 and 32 ° indicating pure carbamazepine form III which were in concurrence with the reported pattern (Lowes et al 1987, York et al 1996). Diffractograms of cocrystal obtained by solvent cooling and crystalline products of USSC trials were identical indicating same crystal structure. Formation of carbamazepine/saccharin 1:1 cocrystal was confirmed by identifying characteristic peak at 2θ = 7° in diffractograms of products of solvent cooling and USSC techniques. No effect was observed on cocrystal formation due to change in sonication amplitude and sonication duration. Sonication resulted in formation, growth, and collapse of bubbles of micrometer-sized dimensions associated with intense, shortly lived heating and pressure i.e. cavitation and acoustic streaming (Suslick 1990, Suslick and Price 1999). This helped to achieve supersaturation at lesser concentration i.e. at saturation concentration, and induced nucleation.

In case of batch F in USSC, uniform supersaturation conditions must have achieved throughout the crystallization vessel at saturation concentration of carbamazepine and saccharin resulting in faster cocrystal nuclei formation and crystal growth i.e. rapid co-crystallization. Further, cocrystal formation did not occur after the concentration at which no supersaturation was achieved due to sonication. The product obtained in batch F was similar as that of other batches, presenting narrow particle size distribution but with low product yield (38 to 43%). The product yield was low as the amount of the cocrystal forming components available in solution for the cocrystal formation was low.

Overlay of carbamazepine, saccharin, and cocrystal Raman spectra was used to identify characteristic peak of caffeine/maleic acid 2:1 cocrystal. Overlay spectra over the range of 300 to 200 cm-1 is shown in figure 3. Carbamazepine/saccharin 1:1 cocrystal exhibited a new peak at 227.2 cm-1 and was considered as its characteristic peak.

The HPLC chromatograms for pure carbamazepine, saccharin and co-crystal are shown in figure 4. Rt of carbamazepine and saccharin was observed at 7.75 ± 0.13 and 1.79 ± 0.14 min, respectively. Calibration curve for carbamazepine and saccharin was found to be linear over the range 5 to 50 µg/ml with regression constant as 0.997 ± 0.004 and 0.992 ± 0.005 respectively. The chromatograms of carbamazepine/saccharin cocrystal obtained by solvent cooling and USSC showed both peaks of carbamazepine and saccharin at respective Rt and no additional third peak was observed. Therefore, no degradation product was observed in chromatogram of cocrystal obtained by USSC. This indicates that sonication has not affected the structural properties of the cocrystal forming components as no third compound is formed neither degradation has been observed.

3.2 Surface characterization

The SEM images for cocrystals obtained by solvent cooling and USSC are shown in figure 5. The particle sizes of cocrystals obtained by solvent cooling were found to be in the rage of 2 to 350 µm, whereas cocrystals obtained by USSC were in narrow size range of 2 to 60 µm. The particle sizes of the co-crystal produced by solvent cooling were found to be dependant on the cooling rate and stirring speed which is in agreement with the previous research (Hicky et al 2007). This may be because of uncontrolled nucleation and crystal growth in solvent cooling.

Alteration in the USSC process variables (concentrations of co-crystal components, sonication amplitude and duration of sonication) did not show any significant effect on particle morphology and size distribution. On the contrary to solvent cooling, faster primary nucleation USSC was observed in USSC, which was fairly even throughout the sonicated volume giving large number of nuclei. These nuclei have a high surface area to volume ratio which after crystal growth presented fine particles with narrower size distribution. Also, excellent mixing conditions created by sonication reduced agglomeration through control of the local nuclei population (Castro and Priego-Capote 2007).

3.3 Solubility and drug release

Saturation solubility data of pure carbamazepine, CBSA-SC, and CBSA-SNC in water is shown in table 4. Aqueous solubility pure carbamazepine was found to be 0.229 ± 0.012 mg/ml which is comparable to reported one (Lee et al 2005). Aqueous solubility of carbamazepine was found to be increased by forming CBSA co-crystal. There was no statistical significant difference between solubility of CBSA-SC and CBSA-SNC. Though the carbamazepine solubility in the form of the co-crystal is increased, it was not statistically significant. Solubility data of pure carbamazepine, saccharin, CBSA-SC and CBSA-SNC in solvent system is shown in table 4. Solubility of co-crystal was analogous with the solid loss in the form of filtrate in SC.

In vitro drug release profiles of pure carbamazepine, CBSA-SC and CBSA-SNC are shown in figure 6. Pure carbamazepine showed only 73% drug release during 180 min in SGF. CBSA-SC and CBSA-SNC were also did not dissolve completely but showed improved drug release (89%) than pure drug which was statistically significant. Though, some difference in release profiles of CBSA-SC and CBSA-SNC was observed, it was not statistically significant. Therefore, results are in accordance with the previous reports explaining that formation of co-crystal of carbamazepine improves its dissolution properties (Hickey et al).

CBSA-SNC demonstrated equivalent potential as that of CBSA-SC with respect to dissolution properties. But, sonoco-crystallization technique possesses advantage over conventional SC with respect to product yield, product characteristics and process feasibility. Processing time required is less in sonoco-crystallization than SC, with higher yield. Also, sonoco-crystallization technique can be operated at lesser concentration of co-crystal forming components (at saturation and lower saturation levels). SC operates only at supersaturation concentrations of co-crystal forming components, where sonoco-crystallization technique possesses lead. The product obtained from sonoco-crystallization technique is with narrow particle size distribution with reproducibility. Processing parameters like sonication amplitude and sonication time or temperature did not show any significant effect on particle size. Whereas, solvent cooling technique gave product with particles with wide particle size distribution which further vary with change in cooling rate and agitation which is in agreement with previous report (hickey et al 2007). This is not the case for sonoco-crystallization technique which did not showed any effect of process variable on particle size distribution. Therefore, sonoco-crystallization technique is more robust one than solvent cooling.

Discussion:

The product yield by both the techniques did not approach to 100%. Yield by SC was less as the co-crystal was formed until the solution had the co-crystal forming components above their saturation concentration; at and below this concentration the co-crystal formation was hampered. These loses were in the form of filtrate; 21 to 31% for SC and 11 to 16% for sonoco-crystallization. The losses were less for sonoco-crystallization technique because of the fact that sonication can achieve supersaturation at lower saturation level. The co-crystal was formed at both the levels when the co-crystal forming components were at supersaturation and saturation concentration. Sonication at saturation concentration had achieved supersaturation leading to formation of the CBSA co-crystal and ultimately gave higher yield as compared to SC. This has been proved from batch F, where the co-crystal was prepared from saturated solution of carbamazepine and saccharin.

Table 1:

Batch code

Saturation level

Sonication amplitude (%)

Time (min)

Product

A

SS

20

5

CC

B

SS

50

5

CC

C

SS

100

5

CC

D

SS

50

1

CC

E

SS

50

3

CC

F

S

50

5

CC

Table 2.

Solvent cooling

USSC

Image surface area

Image projected surface area

Rq

Ra

Image surface area

Image projected surface area

Rq

Ra

1.24 ± 0.34

1.01 ± 0.02

6.10 ± 0.91

4.67 ± 0.59

1.24 ± 0.03

1.05 ± 0.04

9.14 ± 0.74

7.39 ± 0.44

4.15 ± 0.10

4.01 ± 0.05

5.64 ± 0.57

5.12 ± 2.62

4.72 ± 0.04

3.97 ± 0.05

9.34 ± 0.35

7.47 ± 0.13

9.26 ± 0.11

9.12 ± 0.07

7.46 ± 1.32

5.09 ± 0.49

10.23 ± 0.98

9.05 ± 0.06

11.45 ± 2.16

8.14 ± 2.16

26.3 ± 0.52

25.13 ± 0.11

8.88 ± 2.02

6.04 ± 1.09

27.7 ± 3.11

25 ± 0.31

14.7 ± 2.40

10.38 ± 2.14

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