# FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS

Table 5.21: Comparison of orders of in vitro release of amoxicillin trihydrate from tablets of T13.1

 Formulation Regression equations Zero order First order T13.1 y = -3.8595x + 94.464 R² = 0.9997 log y = -0.0356x + 2.0486 R² = 0.9451

Perusal to theFigures 5.13 and 5.14reveals that the formulations did not follow a First-order release pattern but followed the Zero-order equation. The formulation showed a fair linearity, with regression value of 0.9997.

Release Mechanisms
To study the release mechanisms of amoxicillin trihydrate the data of in vitro drug release was verified using Higuchi’s model, Korsmeyer-Peppas model, and Hixon-Crowell cube root law models.

Figure 5.15:In vitrorelease profile amoxicillin trihydrate from tablets of T13.1 fitted in Higuchi’s Plot

Table5.22: Fitting of the Hixon-Crowell cube root law for in vitro release of amoxicillin trihydrate from the tablets of T13.1

 Time (hour) M01/3-M1/3 1 0.291 2 0.456 4 0.682 6 0.967 8 1.333 10 1.643 12 2.032 16 2.966 20 4.217 24 7.785

Figure 5.16: Fitting of the Hixon-Crowell cube root law for in vitro release of amoxicillin trihydrate from the tablets of T13.1

In order to explore more precise mechanism of release of amoxicillin trihydrate from in house developed tablets, the dissolution data was also fitted to the well known exponential equation (Korsmeyer equation) as shown in the Figure 5.17, which is often used to describe the drug release behavior from polymeric systems.

Figure 5.17: In vitrorelease profile of amoxicillin trihydrate from the tablets of T13.1 fitted in Korsmeyer’s Plot.

Table5.23: Regression equations of in vitro release of Amoxicillin trihydrate from the tablets of T13.1

 Formulation T13.1 In vitrorelease of amoxicillin trihydrate from the tablets of T13.1 Higuchi’s model Hixon-Crowel model Korsmeyer Peppas model y = 22.76x - 22.294 R² = 0.9634 y = 0.2787x -0.632 R² = 0.8779 y = 0.7393x +0.9155 R² =0.9887

Application of Hixon–Crowell cube root law, the equation (M01/3 – M1/3) = kt, provides information about the release mechanism, namely dissolution rate limited. Application of Higuchi’s equation (M = K t1/2) provides information about the release mechanism, namely diffusion rate limited. Korsmeyer-Peppas model indicates that release mechanism is not well known or more than one type of release phenomena could be involved. The 'n' value could be used to characterize different release mechanisms as:

Table5.24: Slope of Korsmeyer-Peppas equation and proposed release mechanisms

 Slope ( n ) Mechanism <0.5 Fickian diffusion (Higuchi Matrix) 0.5

The data of average values were processed as per Hixon-Crowell cube root law and are given in the Tables 5.22 and the Figure 5.16. The data of average values were processed as per Higuchi’s equation and are represented in the Figure 5.15. The data of average values were processed as per Korsmeyer-Peppas model and are represented in the Figure 5.17. The linearity of data for all the models was identified from the Figures. The equations were generated through statistical procedures and reported in the Table 5.23.

Perusal to the Table 5.23 indicates that R2 values are higher for the Higuchi’s model compared to Hixon – Crowell for the tablets of T13.1. Hence amoxicillin trihydrate release from the tablets of T13.1 followed diffusion rate controlled mechanism.

According to Korsmeyer-Peppas model,a value of slope is between 0.5 to 1.0 indicates the Non-Fickian diffusion and hence release mechanism from tablets of T13.1follows Non-Fickian diffusion.

Accelerated stability study
Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic, and toxicological specifications.

Tablets of T13.1 were kept for accelerated stability study at 40 + 2oC and 75 + 5% RH for 1 month in the modified stability chamber.

After a period of one month, the samples were observed for any change in physical parameters.  It was observed that surface was devoid of any change in color or appearance of any kind of spots on it.  It was also noted that surface was free of any kind of microbial or fungal growth or bad odor.  No changes in the smoothness of the tablets were noted.  The drug content of the formulations was found 98.03% for tablets of T13.1, which shows that, there is no decrease in drug content and difference is insignificant.  The in vitro release of the samples after one month storage compared with release profile of sample at zero are shown in the Table 6.25 for  T13.1. Graphical representations are shown in Figure5.18.

Table 5.25:  In Vitrorelease of amoxicillin trihydrate from tablets of T13.1 on zero day and samples after one month accelerated stability studies

 Time (hours) Cumulative percentage of drug released (%) Tablets of zero day Tablets after one month 1 9.1+ 0.72 8.78+ 0.65 2 14.0+ 0.61 13.29+ 0.84 4 20.4+ 0.44 21.00+ 0.28 6 27.99+ 0.19 26.32+ 0.31 8 37.01+ 0.15 38.23+ 0.11 10 44.0+ 0.28 43.84+ 0.77 12 51.99+ 0.64 52.00+ 0.83 16 67.89+ 0.82 66.27+ 0.64 20 82.78+ 0.91 81.99+ 0.51 24 97.72+ 0.37 96.04+ 0.80

Figure 5.18: In vitrorelease of amoxicillin trihydrate tablets from T13.1 on zero day and after one month of accelerated stability studies

By comparison, it was found that after a period of one month of storage there were no changes in the physical as well as drug release profiles of the tablets of both the batches and both were imitating the same drug release pattern. The f1 and f2 values in the comparison of release before and after one-month storage (at accelerated conditions) were found 1.79 and 91.76 respectively for tablet (T13.1).

CAPSULE
Development of the formulation in the present study was mainly based on the type of polymer, concentration of polymers, and the drug. Various polymers and excipients in different combinations were used so as to get desire in vitro drug release from tablet. Amoxicillin trihydrate is water soluble drug, and dose taken is 775 mg. So, in the present study attempts were made to get capsule with desire drug release profile of the capsule.

Manufacture of capsule
As described in the methodology chapter the, Granules prepared by wet granulation method by mixing ingredients given in the table 4.11, compress it in tablet form with higher hardness. Crush tablet and pass it from sieve 14#. Fill it in a 00size hard gelatin capsule shell by using hand operated capsule filling machine.Different polymers were used in different concentrations to get good release of drug.  Different excipients like delayed release polymer, coating material, lubricants were used to get good drug release.

Table 5.26: Uniformity of weight and drug content of capsule formulations C1 to C6

 Formulations Uniformity of weight of net content(gm) Drug content (%) (n=3) C1 1.065+ 7.5% 97.02+ 0.52 C2 1.212+ 7.5% 97.32+ 0.21 C3 1.300+ 7.5% 98.00+ 0.11 C4 1.044+ 7.5% 97.98+ 0.73 C5 1.054+ 7.5% 97.99+ 0.85 C6 1.10+ 7.5% 98.76+ 0.29

Dissolution profile of the capsules for the batches C1 to C6
After getting uniformity of weight of net content and drug content satisfactory for batches C1 to C6, the dissolution of these batches was tested. Dissolution was carried out as per the procedure mentioned in methodology chapter. The details of the dissolution study for the capsules of the batches C1 to C6 are given in the Table 5.27 and in Figure 5.19.

Table 5.27: In vitro release of Amoxicillin trihydrate from capsules of batch C1 to C6

 Time (hrs) Cumulative percentage of drug released (%) C1 (n=6) C2 (n=6) C3 (n=6) C4 (n=6) C5 (n=6) C6 (n=6) 1 92.71+ 0.61 94.03+ 0.52 83.00+ 0.32 36.08+ 0.11 25.23+ 0.30 20.63+ 0.28 2 - - 97.01+ 0.67 67.91+ 0.38 38.34+ 0.21 31.28+ 0.15 4 - - - 96.45+ 0.63 49.65+ 0.66 45.37+ 0.62 6 - - - - 62.88+ 0.82 53.45+ 0.85 8 - - - - 78.62+ 0.62 66.27+ 0.49 10 - - - - 86.13+ 0.44 71.83+ 0.64 12 - - - - 97.24+ 0.17 84.00+ 0.39 16 - - - - - 98.11+ 0.13 20 - - - - - - 24 - - - - - -

Figure 5.19:Comparison of in vitro release of Amoxicillin trihydrate from the capsules of the batches C1 to C6 with theoretical drug release profile.

Drug release profile of any of the formulations mentioned above did not appear to be closer to the theoretical drug release profile. As C1 showed 92.71 % in 1 hour, C2 showed 94.03% in 1hours, C3 showed 97.01 % in 2 hours, C4 showed 96.45 % in 4 hours, C5 showed 97.24 % in 12hours, C6 showed 98.11 % in 16hours. This indicates that no formulation is showing acceptable drug release profile as theoretical profile. This could be because in C1 formulation batch there was only used coating material for drug release and no delayed release polymer used. So granule was quickly dissolved and drug release so fast. It could not be extend up to 24 hours. Batch formulation C2 made only by using delayed release polymer HPMC K4M and drug. But it also could not be extend up to 24 hours. In formulation C3, coating is only more thing than the C2 showed no more drug release extend. In formulation C4 there was using directly high concentration of polymer i.e. 8% ethyl cellulose. But it also fails to extend drug release. In C5 formulation, there was 15% ethyl cellulose polymer used. But it only extends drug release up to 12hours. Finally in C6 formulation, there was 20% polymer used. But drug release only extends up to 16hours. However it was more than C5 formulation. But initial drug release was found to be more as compared to theoretical drug release profile. And if again add more concentration of the polymer then it can not fill in to even two 00size of capsule.

So, all formulation fails to match drug release with theoretical drug release profile. Capsule formulation was found to be not optimized. Capsule formulations not extend up to 24hrs drug release, so it not needs to compare with the tablet formulation.

Review of Literature
The chapter “Literature Review” contained review on drug and excipients. Extensive literature survey was done on dosage forms of amoxicillin trihydrate for selection of polymer, excipients, and method of manufacturing. A detailed description about amoxicillin trihydrate, polymer, and excipients were discussed.

Methodology
In order to solve the objectives of this work, suitable analytical method (UV Spectroscopy) was established and validated in distilled water, 50mM of potassium phosphate monobasic buffer at pH 4, 6 and 6.8 buffer solutions. Physical properties of Amoxicillin trihydrate and polymers like loose bulk density, tapped bulk density, compressibility index and angle of repose were determined. Formulations for amoxicillin trihydrate 775mg tablets and capsules were developed and were evaluated for pharmacopoeial and nonpharmacopoeial (industry specified) tests.  Polymer and concentration of polymer were optimized for tablets. And it also tried for the capsule dosage forms. Tablet and capsules were prepared with different polymers like HPMC (K4M), ethyl cellulose, methocel, and coating material in order to optimize one final formula for dosage form. Tablets were evaluated for physical and chemical properties.  For tablets in vitro release was carried out in distilled water for 24 hours using USP type II apparatus at 100 rpm. Capsule evaluation like weight uniformity, drug content and in vitro drug release were also done. Short term accelerated stability study of optimized formulations of amoxicillin trihydrate 775mg tablets were carried out at 40 + 2 oC and 75 + 5% RH for one month.

Results and discussion
The results and discussion of different methods of this thesis were described under different headings using graphs and tables.  No interference due to additives in the estimation of amoxicillin trihydrate was observed (Figures 5.1 to 5.6).  Different polymers were used to get a suitable formulation of tablets and capsule and finally were optimized to get optimized formulations. The optimized formulation consists of methocel and ethyl cellulose polymer. Tablets were evaluated for pharmacopoeial and nonpharmacopoeial (industry specified) tests and were found to be within the prescribed limits. Amoxicillin trihydrate tablets were prepared with different formulae for optimized formulations that show f1and f2in prescribed limits when using theoretical drug release profile as reference standards.  The average f1 and f2 values of optimized formulation were found to be 1.75 and 92.37 for tablets respectively. The R2 = 0.9997 (figure 5.13) for the zero order release and for first order release R2 = 0.9451 (figure 5.14). Hence the release of amoxicillin trihydrate from developed formulations was considered to be zero order.  The Higuchi’s equation showed R2 = 0.9634 (figure 5.15) and also when the data was fitted in to Korsmeyer et al equation it showed R2 = 0.9887 (figure 5.17) with slope (n) value of 0.7393 which is between 0.5 and 1.0. Thus, diffusion of the drug was the main mechanism for drug release for the optimized formulation.  Formulation was found to be reproducible and stable for one month under accelerated stability condition. Capsule evaluation of weight uniformity and drug content was found to be passed but it fails in in vitro drug release test. And drug release found to be extending only up to 16hrs not up to 24hrs. So capsule was found to be not optimized formula.

Conclusions
The conclusions drawn from the present investigation were given below;
1.    Suitable analytical method based on UV-Visible spectrophotometer was developed for amoxicillin trihydrate.  ?maxof 272.6nm, 272.2nm, 272.8nm and 272.6nm nm and were identified in distilled water, 50mM potassium phosphate monobasic buffer at 4 pH, at 6 pH solution and at 6.8 pH buffer solution respectively.
2.    From the FT-IR spectra the interference was verified and found that amoxicillin trihydrate did not interfere with the excipients used.
3.    Procedure to manufacture tablets and capsules by different method was established.
4.    Tablets of amoxicillin trihydrate (T13.1) were successfully prepared using ethyl cellulose (50%) and methocel (50%) by wet granulation method.
5.    The tablets were evaluated for pharmacopoeial and non-pharmacopoeial (industry specified) tests.  Based on the results, T13.1 was identified as better formulation amongst all formulations developed for tablets.
6.    Tablets of the formulation T13.1 passed all official and unofficial quality control tests.
7.    In vitro release profiles of optimized formulations of amoxicillin trihydrate tablets (T13.1) were found to be similar to that of theoretical drug release profile. The f1 and f2 values for the comparison of release of drugs from the formulation T13.1 with the theoretical drug release profile were found to be 1.75 and 92.37respectively, for tablets.
8.    The manufacturing procedure was standardized and found to be reproducible. The f1 and f2 values for the comparison of release of drugs of first and second (reproducible) trial were found to be1.97 and90.75respectively for the tablets of the formulation T13.1.
9.    Amoxicillin trihydraterelease from the tablets of T13.1 formulation follows zero - order kinetics.
10.    Amoxicillin trihydrate release from the tablets of T13.1 formulation follows Higuchi model.
11.    Release mechanism of amoxicillin trihydrate from tablets of T13.1 formulation follows Non-Fickian diffusion.
12.    After one month of accelerated stability studies developed formulation was found to be stable. The f1 and f2 values in the comparison of release before and after one-month storage (at accelerated conditions) were found to be1.79 and 91.76for the tablets of the formulation T13.1.
13.    Capsules of amoxicillin trihydrate were prepared using ethyl celluloseand methocel by slugging method.
14.    The capsules were evaluated for weight uniformity, content uniformity and in vitro drug release.
15.    Capsules of the formulation were passed the weight uniformity and drug content test but fails to in vitro drug release test.
16.    In vitro drug release of the capsule formulation C6 only up to 16hours not to 24hours.
17.    In comparison of tablet and capsule formulation, tablet was found to be successful formulation as compared to tablet dosage form.

The conclusions arrived in this thesis indicated that the modified release tablet of amoxicillin trihydrate developed in this investigation releases drug equivalent to theoretical drug release, based on in vitro release studies.

Further studies are needed to investigate these formulations for its performance in vivo. Capsule formulation also tries by using different method like extrusion spheronisation method etc.
Thus the objectives of the present thesis are achieved.
The result of the study indicates that modified release tablets of amoxicillin trihydrate that can be successfully prepared.

Appendix A

List of abbreviations
API    Active Pharmaceutical Ingredient
Avg.    average
E.g.    Example
EC     Ethyl Cellulose
EP     European Pharmacopoeia
ER     Extended Release
f1      Difference factor
f2      Similarity factor
FT-IR    Fourier transform infrared spectroscopy
GI      Gastro Intestinal
GIT    Gastro Intestinal Tract
HCl    Hydrochloric acid
HPMC    Hydroxy Propyl Methyl Cellulose
hrs    Hours
ICH    The international conference on harmonization of technical requirements for registration of pharmaceuticals for human use
IP     Indian Pharmacopoeia
IR     Immediate Release
LBD    Loose Bulk Density
MCC    Microcrystalline cellulose
MIC    Minimal Inhibitory Concentration
MR    Modified Release
PBP    Penicillin Binding Protein
PVP    Polyvinyl Pyrrolidone
RH     Relative Humidity
rpm    rotations per minute
RT     Retention Time
SD     Standard Deviation
Sec.   Seconds
Std.    Standard
TBD    Tapped Bulk Density
UDP    Uridinediphosphate
USP    United State Pharmacopoeia
Wt.     Weight

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