COMPARATIVE IN-VITRO MULTIMEDIA DISSOLUTION STUDY OF CARBAMAZEPINE EXTENDED RELEASE TABLET 400MG AT VARIOUS PH RANGE

Author : Jignesh Shah, Vrunjan Shah, Deepika Koul, Aryan Gupta, Akash Goswami, Amit Patel, Dharmesh Shah, Kaushik Shah

Page Nos : 01 - 14

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  1. Introduction

Carbamazepine contains dibenzepine ring system which is structurally related to the tri-cyclic antidepressants [1–4] specifically used in therapy for seizures. Carbamazepine is highly insoluble in water at ambient temperature (25ºC) [5–8] with a solubility of 170mg/l. As the Carbamazepine is representing low water solubility, its bioavailability is also very low. Also polymorphism is observed for carbamazepine, which may affect its solubility. Upon multiple dosing of carbamazepine, it gets transformed to its metabolite and its half-life (t1/2) is decreased [9]. The research says that central nervous system (CNS) side effects, related with immediate-release formulation of carbamazepine were reduced when patients were moved to an extended-release formulation [10]. So, sustained release formulation of carbamazepine is most effecting in maintaining the concentration in systemic circulation [9].

1

Figure-1 Carbamazepine Chemical Structure

Literature described the transformation of one polymorphic form to another dihydrate form, which is showing variable dissolution

behavior of carbamazepine [11–13]. There have been several reports showing irregular dissolution [14–16], bioequivalence failures [17–19], and clinical failures of carbamazepine [20]. Certain literatures have been found which indicates the impact on polymers to make the drug release profile prolonged. But the optimization of polymer levels and combination of polymers plays a foremost role in achieving a successful extended release formulation which is correlating with the innovator formulation in each dissolution medium i.e. original medium as well as different biological pH.

In general, the enhanced dissolution pattern is depending upon either by dissolution medium pH change or by addition of the solubilizer, like surfactants and cyclodextrin derivatives in the preparation of dissolution medium [21–27]. SLS has been proven as the agent of choice because it is cost-effective and it holds good solubilizing capacity even at quite low concentrations. Already, several authors reported that SLS can be used to enhance dissolution of low water-soluble compounds [28]. Till date, many authors had published the articles on the addition and usage of SLS like sodium taurocholate or other surfactant for executing the dissolution of low soluble drug like carbamazepine using less dissolution media volume. Carbamazepine solubility was also distinctly increased in several nonionic surfactants [29]. But with the medium volume 1800mL according to USP method, very few articles were present which shows the surfactant assisted dissolution to get the higher release profile.

Even the data of innovator formulation in original medium as well as in the acidic medium has not been described at a large extent.

But here, the aim of carrying out the in-vitro drug dissolution at various biological pH to partially evaluate the effect of pH on drug release and absorption during in-vivo conditions. And specifically to evaluate the effect of surfactant on drug release and to set t h e mi n imum p o ssi b l e o p timum concentration of surfactant to achieve desired drug release with a minimum variability in the results of both – innovator as well as test formulations.

2.  Experimental

2.1  Chemicals and materials

Carbamazepine working standard (99.74%) was prepared from an API – Form-III, against a reference standard (99.9%) (B. No. 5) procured from EDQM. Methanol (HPLC grade, Merck, India), Hydrochloric acid (GR Grade, Merck, India), Sodium Chloride (GR Grade, Merck, India), Sodium Lauryl Sulphate (Emplura Grade, Merck, India), Sodium Hydroxide (GR Grade, Merck, India), Sodium Acetate (GR Grade, Merck, India), Acetic acid (GR Grade, Merck, India) and Potassium Dihydrogen Phosphate (GR Grade, Merck, India) were used for in-vitro dissolution experiments. Formulation of two different batches of innovator (RLD) product – Tegretol LP 400mg (Mfg. By: Novartis) were procured for comparing the release profile of test formulation.

2.2 Instrumentation

A dissolution apparatus system (708-DS, Agilent, Germany) with closed autosampler (850-DS, Agilent, Germany) with a 2 Liter bowl capacity, Double Beam UV Spectrophotometer (UV-1800, Shimadzu, Japan), Portable Dissolved Oxygen (DO) meter (HI9146, Hanna Instruments, Italy), Micro analytical balance (MSA6-6S-000- AM, Sartorius, Japan), pH meter (Thermo Orion Star II, Thermo, USA), Water purification system (Milli-Q, Millipore, USA), Dissolution Media Preparation Assembly and RO water system were used for dissolution experiment.

2.3 Instrumental method parameters

For carrying out dissolution experiment, USP dissolution apparatus – I (rotating basket with mesh size 10) with 2 liter capacity bowl were used. RPM of instrument was set to 100. The temperature of the medium was set to 37±0.5°C. 1800mL of dissolution medium was filled in each bowl [30]. Using a cannula with 70µ PTFE filter, 10mL sample from each bowl was withdrawn by auto-sampler connected with the dissolution apparatus and with PC. Same way, after withdrawal, 10mL of the respective medium was transferred to each bowl as media replacement to maintain the same volume throughout the experiment. The method was created in the computerized program to run the experiment. Standard and samples were analyzed through UV spectrophotometer using the wavelength 284nm.

2.4 Analytical Procedure

 2.4.1 Standard and sample preparation

The carbamazepine working standard was weighed about 22.4mg and transferred to 100mL volumetric flask and dissolved in 25mL of methanol. Final volume was achieved with respective dissolution medium. After mixing, transferred 1mL of this solution to 25mL volumetric flask and diluted up to the mark with the respective medium.

The withdrawn samples were transferred to respective glass tubes kept inside the autosampler unit. 2mL of each sample was transferred to 25mL volumetric flask and diluted up to the mark with the respective medium.

UV Probe software was used from a computer which is connected with UV Spectrophotometer, and wavelength was set at 284nm. Initially, using respective dissolution medium, absorbance was corrected to zero. After correction, diluted standard solution was taken and analyzed. After that, diluted samples of each unit and each time points were analyzed. From the

absorbance values, the % cumulative drug release of all units at each time point were calculated and evaluated for the acceptance of experiment (% drug release and %RSD).

2.5 Method development & optimization

For developing a generic formulation of Carbamazepine Extended Release Tablet with strength 400mg, from a reference of USP, it was found that dissolution should be performed with a media volume of 1800 mL to achieve the sink condition due to BCS Class-II drug. In its defined media – water, the dissolution profile of drug release from innovator formulation was observed for 24 hours and found reproducible within the acceptance level. In same manner, the test formulations were manufactured with different formulas according to QbD approach to match the drug release profile comparable to innovator formulation.

Initially analytical dissolution method was set according to USP using UV spectrophotometer. UV spectrum of Carbamazepine was scanned throughout the UV range. The 284nm was observed max which was also correlated to the given value in USP(Refer figure-2).

2

Figure-2 UV absorption spectrum of Carbamazepine

During the execution of experiment, behavior of innovator formulation was varying for each experiment and within the intra-units of respective individual experiment. To overcome this situation, the dissolution medium was degassed completely and dissolved oxygen was continuously monitored before the start of the experiment. Upon achieving the dissolved oxygen value below 5, medium was taken for the experiment. After that, the tablets of two different batches of innovator were evaluated with multiple experiments and results were found

satisfactory with respect to drug release and %RSD. Once the innovator profile has been evaluated, the formulation trials were started simultaneously and same were evaluated for drug release profile. After evaluation of release profile of all the formulations in water as a dissolution medium, the best formulation was selected and release profile was matched with innovator profiles. Table-1 represents the drug release profile of both batches of innovator formulation and the final test formulation in water.

Table-1 Drug release profile of both batches of innovator

formulation and final test formulation in water

Sr. No. B. No. 1 2 3 4 5 6 7 8 9 10 11
1 Hr 2 Hr 3 Hr 5 Hr 6 Hr 8 Hr 10 Hr 12 Hr 16 Hr 20 Hr 24 Hr
 
RLD
1 RLD(B-1) % Release 13.5 21.7 29.5 43.0 48.9 58.9 66.4 72.5 80.5 84.8 88.7
%RSD 2.1 5.0 3.6 3.7 3.9 4.1 3.0 3.1 2.9 2.4 2.9
2 % Release 13.4 22.2 30.0 43.5 49.8 59.3 66.9 72.9 81.7 86.4 89.7
%RSD 7.3 6.5 6.7 5.2 4.4 4.4 4.8 3.4 3.6 2.4 1.7
3 RLD(B-2) % Release 14.3 24.7 33.5 48.3 54.3 63.2 69.5 73.0 78.6 81.8 83.2
%RSD 8.2 5.7 4.3 4.1 4.8 3.3 3.5 3.2 3.1 3.7 3.5
4 % Release 18.7 29.7 37.6 50.1 54.9 62.5 67.3 73.3 79.4 84.7 84.4
%RSD 3.6 7.0 4.2 4.8 4.4 3.4 2.8 2.5 1.7 1.7 1.1
TEST
1 Test(B-1) % Release 15.6 24.9 32.5 44.9 49.7 59.2 65.7 71.2 79.3 84.5 88.4
%RSD 3.5 2.6 2.2 1.4 1.0 1.5 1.5 1.8 2.0 2.5 2.9
2 % Release 15.5 24.6 32.1 44.3 49.7 58.1 64.8 71.0 79.3 83.7 87.0
%RSD 4.5 4.1 3.0 3.3 3.5 3.1 2.8 3.3 3.3 3.4 2.6

Results represented that the profile of both formulation were found equivalent. Similarity factor (f2) for the 6 units as well as 12 units was found above 50. Table-2

represents the f2 value of experiments in water with multiple variables (Experiments, Batch, Formulation – Innovator or Test etc.).

Table-2 Similarity factor (f2 value) of experiments in water with multiple variables

F2 Value RLD-1 – EXP-1 RLD-1 – EXP-2 RLD-2 – EXP-1 RLD-2 – EXP-2
TEST-1 – EXP-1 85.3 84.3 74.5 71.1
TEST-1 – EXP-2 85.1 82.3 73.9 69.8

To meet the requirements of similar formulation, in-vitro dissolution studies to be performed and evaluated in all the biological pH media i.e. at pH 1.2, 4.5 & 6.8 in addition to original medium – water. On those circumstances, the in-vitro drug release profiles were evaluated with innovator formulation and test formulation at dissolution medium of all respective pH.

During start with the medium at pH 1.2, the drug release profile of innovator formulation was found very typical with respect to % drug release and %RSD. The release of carbamazepine in intra units were differing at a large extent with an overall value lower than that of observed in water. The intra-units drug particles variation was observed in the dissolution medium, which might be the reason for creating the problem in reproducibility of drug release at each time interval. To

overcome and understand this, the dissolution bowls were continuously monitored for specific observations during dissolution cycle. During monitoring it was observed that, the tablets were disintegrated within 0.5 to 1 hour and particles were found rotated within the medium. But during 1 to 4 hours, the tablet particles were agglomerated and stick to bowl at one side without rotating under the basket. These phenomena occurred nonuniformly, means sometimes in all bowls while sometimes in only few of them. And results would be affected as per the behavior of particles movement in the medium. Figure-3 represents the particle behavior during dissolution cycle in water and acidic medium. Figure-4 represents the intra-units particles behavior during dissolution cycle in acidic medium with variability in 3rd unit from other 5 units.

3

Figure-3 Particles behavior during dissolution cycle in water (a) and acidic medium (b)

4

Figure-4 Intra-Units particles behavior during dissolution cycle in acidic medium

Upon continuous experiments and observations, it was also noted that more the particle were rotating in the medium, more the drug release was observed in that bowl. And whenever the particles were stick to bowl surface in the initial hours, same situation would remain throughout the cycle and results would not be

achieved at higher side with uniformity. The aforementioned phenomena was occurred for both type of formulations i.e. innovator as well as test. Table-3 represents the dissolution profile in acidic pH 1.2 HCl buffer with a non-uniform lower release and with a high variability in both formulations – innovator and test.

Table-3 Drug release profile and variability in innovator formulation and final test formulation in acidic pH 1.2 HCl medium

Sr. No. B. No. 1 2 3 4 5 6 7 8 9 10 11
1 Hr 2 Hr 3 Hr 5 Hr 6 Hr 8 Hr 10 Hr 12 Hr 16 Hr 20 Hr 24 Hr
 
RLD
1 RLD(B-1) % Release 9.7 15.9 20.0 28.5 32.1 37.9 42.7 46.5 50.8 57.1 64.2
%RSD 14.3 20.8 25.0 30.2 31.8 32.6 33.4 32.6 30.0 24.1 24.0
2 % Release 9.1 14.8 20.8 31.0 34.9 42.2 48.2 53.6 62.3 68.9 72.5
%RSD 10.3 16.3 20.0 22.9 26.4 26.2 26.1 23.8 20.7 20.0 19.0
3 % Release 8.5 13.9 20.0 32.7 39.0 49.1 56.6 62.4 71.4 78.2 82.0
%RSD 10.7 13.3 15.4 12.4 8.0 5.0 4.4 3.0 2.7 2.5 2.0
4 % Release 9.0 14.2 18.6 25.9 28.5 33.2 37.7 41.4 46.5 52.0 55.9
%RSD 13.2 22.1 26.7 31.9 32.0 32.0 32.8 31.6 30.0 27.2 25.2
5 % Release 12.0 17.5 22.4 30.0 33.2 38.3 42.5 46.4 52.0 56.3 60.0
%RSD 4.5 15.8 22.7 33.6 36.9 41.8 44.4 44.2 43.5 42.0 39.9
TEST
1 Test(B-1) % Release 14.0 22.9 29.7 40.5 45.0 51.9 58.3 63.3 71.2 78.2 81.0
%RSD 5.6 4.9 5.7 7.3 7.6 9.7 9.7 10.4 11.8 12.2 12.1

However, the in-vitro experiments were continued in dissolution medium at other pH i.e. 4.5 and 6.8. Innovator and finalized test formulations in-vitro dissolution were performed and evaluated. No variability in intra-units as well as repeated experiments

were generated in any of the dissolution mediums. At both pH levels, the similarity factor (f2) was evaluated and found above 50. Table-4 represents the f2 value of multiple experiments in both pH medium.

Table-4 Similarity factor (f2 value) of multiple experiments in pH 4.5 and 6.8 medium

F2 Value pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer
RLD-1 – EXP-1 RLD-1 – EXP-2 RLD-1 – EXP-1 RLD-1 – EXP-2
TEST-1 – EXP-1 78.7 87.8 71.3 57.6
TEST-1 – EXP-2 84.6 85.5 78.5 85.7

So, to overcome the dissolution variability in acidic pH and based on the literature (ANDA applications [31,32] & USP Pharmacopeia [33]) for using a surfactant – SLS, the experiment was performed in the dissolution medium with addition of a little quantity of surfactant (0.07%w/v) in it. The experiment was performed in the acidic medium with lower concentration of

surfactant and the results were evaluated. Still there was no more improvement observed in the variability of drug release. So, after 3 initial points the experiment was discontinued. Table-5 represents the variability in the initial time points during dissolution of innovator formulation with lower concentration of surfactant in acidic medium.

Table-5 Drug release and variability in innovator formulation with lower concentration of surfactant (0.07%w/v) in acidic pH 1.2 HCl medium

Sr. No. B. No. 1 2 3 4 5 6 7 8 9 10 11
1 Hr 2 Hr 3 Hr 5 Hr 6 Hr 8 Hr 10 Hr 12 Hr 16 Hr 20 Hr 24 Hr
 
RLD
1 RLD

(B-1)

% Release 12.8 21.6 42.2 - - - - - - - -
%RSD 7.2 18.9 23.6 - - - - - - - -

To rectify this variability issue, concentration of surfactant was increased (0.1%w/v) in acidic medium and again the innovator and test formulation were taken for dissolution experiment. The results were found very satisfactory with respect to intra-units similar behavior as well as %

drug release of carbamazepine at each time interval. As the repeated results were found reproducible for both – innovator and test formulations, further trials with higher concentration of surfactant are not required. Figure-5 represents the particle behavior during dissolution cycle in acidic medium with 0.1%w/v surfactant.

5

Figure-5 Particles behavior during dissolution cycle in acidic medium with 0.1%w/v surfactant

The in-vitro dissolution in surfactant aided acidic medium was re-performed using a new batch of innovator formulation and multiple experiments using same batch of final test formulation. Table-6 represents the dissolution profile in acidic pH 1.2 HCl buffer with optimized concentration of

surfactant (0.1%w/v) for both formulations – innovator and test. The similarity factor was found above 50, which is acceptable. Table-7 represents the f2 value of multiple experiments in acidic pH medium with optimized concentration of surfactant (0.1%w/v).

Table-6 : Dissolution profile of both formulations innovator and test in acidic pH 1.2 HCl buffer with 0.1%w/v surfactant

Sr. No. B. No. 1 2 3 4 5 6 7 8 9 10 11
1 Hr 2 Hr 3 Hr 5 Hr 6 Hr 8 Hr 10 Hr 12 Hr 16 Hr 20 Hr 24 Hr
 
RLD
1 RLD

(B-1)

% Release 14.1 24.2 34.9 55.7 63.8 75.4 82.3 86.4 91.4 93.7 94.2
%RSD 6.6 7.6 8.9 5.6 4.7 2.6 2.5 2.3 1.5 2.6 1.8
2 % Release 13.7 23.8 34.9 55.4 63.7 74.4 81.5 85.6 90.3 92.4 93.4
%RSD 7.5 8.0 8.2 5.2 4.6 4.1 3.4 2.9 2.7 2.8 2.2
3 RLD

(B-2)

% Release 15.0 27.0 39.6 60.6 67.5 77.3 83.0 86.4 90.1 93.0 92.2
%RSD 8.6 9.8 9.3 4.7 4.0 2.6 1.2 1.6 0.5 0.7 0.5
4 % Release 14.4 26.6 39.1 59.7 65.9 75.0 80.7 84.3 87.8 89.2 91.4
%RSD 7.2 7.5 7.7 3.9 3.2 1.3 1.6 1.6 1.8 1.7 1.7
TEST
1 Test

(B-1)

% Release 18.6 30.9 41.5 58.2 65.4 75.1 82.5 87.6 94.2 97.4 97.8
%RSD 2.9 1.8 3.2 2.6 2.0 1.5 0.8 1.5 1.9 1.5 2.9
2 % Release 18.3 29.9 39.3 54.9 60.3 70.0 77.7 82.9 89.9 93.6 96.2
%RSD 2.2 4.3 4.8 4.2 3.9 4.1 3.9 3.4 2.7 3.1 3.5
3 % Release 18.9 31.1 41.4 55.2 63.2 77.1 84.5 85.8 88.8 91.8 94.5
%RSD 5.0 4.4 4.1 5.1 3.2 0.8 1.4 1.3 0.8 0.6 0.7
4 % Release 18.9 30.1 40.0 55.5 62.0 71.7 80.6 85.6 88.7 92.6 94.5
%RSD 4.4 2.0 1.9 1.1 1.4 1.4 1.1 0.7 0.8 0.7 0.5

Table-7 Similarity factor (f2 value) test in acidic pH 1.2 HCl buffer with 0.1%w/v surfactant

F2 Value RLD-1  EXP-1 RLD-1  EXP-2 RLD-2  EXP-1 RLD-2  EXP-2
TEST-1  EXP-1 70.5 68.9 77.1 68.8
TEST-1  EXP-2 70.1 71.2 67.1 70.6
TEST-1  EXP-3 70.4 69.4 74.3 73.8
TEST-1  EXP-4 71.8 72.3 71.0 74.9

3. Results and discussion

All the obtained results of in-vitro dissolution experiment were compared with each other with respect to formulation and medium pH. The in-vitro release results showed the repeated results similarity with intra-day precision when experiments were performed in water, pH 4.5 and pH 6.8 buffers, but when the experiments were performed in acidic medium, variability was observed in intra-units of a same experiment. This high variability was studied and resolved with the use of surf a c t ant a t a lowe st optimum concentration (0.1%w/v) for only acidic medium. Similarity factor (f2 value) was found above 50 for all the respective experiments with multiple batched of innovator, which proved the reproducibility of results with an acceptable variability.

4. Conclusions

In acidic medium, the results with 0.07%w/v concentration of surfactant was showing release with variability whereas results with 0.1%w/v concentration of surfactant was showing enhanced drug release with acceptable variation for both – innovator as well as test formulation. So, for in-vitro dissolution profile study in acidic medium, 0.1% w/v of SLS as a surfactant was finalized to use to get the desired improved release profile with negligible variability at a minimum optimized concentration.

5. Acknowledgments

Authors are thankful to all scientists and the team members of Sushen Medicamentos

Pvt. Ltd for uninterruptedly delivering the best performance in executing the dissolution of 24 hours cycle under complete observations. Authors are also thankful to the administrative team members for providing all the resources on time for carrying out this work. In same manner, authors are also thankful to the management of Sushen Medicamentos Pvt. Ltd., for providing the support to complete this work.

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