Enhancement of Dissolution Rate of Cefpodoxime Proxetil by Using Solid Dispersion and Cogrinding Approaches

 

S. Duraivel¹*, V. Venkateswarlu², Ammula Praveen Kumar³, Harish Gopinath¹

¹Department of Pharmaceutics, Nimra College of Pharmacy, Jupudi, Ibrahimpatnam, Vijayawada, Andhra Pradesh, India.

²Formulation Research and Development, Reddy’s Laboratories, Hyderabad, Andhra Pradesh, India.

³Department of Pharmaceutics, Jayamukhi College of Pharmacy, Narsampet, Andhra Pradesh, India.

 

ABSTRACT:

Cefpodoxime proxetil (CP) have the poor aqueous solubility due to its metabolic degradation in lumen, hence dissolution is the rate limiting step for poorly soluble drugs. In present study, in order to enhance the drug dissolution rate of CP by solid dispersion using carriers such as polyethylene glycol 6000, polyvinylpyrrolidine K30 and co-grinding mixtures with carriers such as sodium starch glycolate, croscarmellose sodium and polyplasdone XL by varying the drug  to carrier ratios. The dissolution rate of CP from solid dispersions and co-grinding mixtures were measured and found to be around 55-70%. The formulated solid dispersion and co-grinding mixture was characterized by FT-IR spectroscopy, DSC, SEM and X-Ray diffraction method. In-vitro dissolution rate of CP from the solid dispersion with PVP K30 at the ratio of 1:4 and co-grinding mixtures with Croscarmellose Sodium (CCS) at the ratio of 1:4 was significantly greater compare to that of the pure drug. The dissolution rate of the drug was affected by nature and the amount of polymer used. FT-IR spectroscopy demonstrated no detectable interaction between the drug and carrier. The DSC and XRD studies indicated amorphous state of the CP from solid dispersion and co-grinding mixtures. The SEM images have shown the formation of effective solid dispersion and co-grinding mixtures, since well defined changes in the surface nature of CP. Thus, solid dispersion and co-grounding approaches can be successfully used for the enhancement of dissolution profile of the drug CP.

 

 

1. INTRODUCTION:

Solubility is a crucial and limiting step for oral drug bioavailability, particularly for drugs with low gastrointestinal solubility and low permeability. By improving the dissolution profile of these drugs, it is possible to enhance their bioavailability and reduce side effects (Leuner, C., et al., 2000). Solid dispersions (SDs) are one of the most successful strategies to improve dissolution rate of poorly soluble drugs. SDs can be defined as molecular mixtures of low water soluble drugs in hydrophilic carriers, which present a drug release profile that is driven by the polymer properties. (Chiou, WL., et al., 1971) CP is an orally administered, extended spectrum, semi-synthetic, ß-lactam antibiotic of the cephalosporin class. The active moiety is in pro-drug form which is de-esterified in-vivo to its active metabolite cefpodoxime by gastrointestinal wall esterase.

 

Absolute bioavailability of CP administered as a 130 mg tablet (equivalent to 100 mg of cefpodoxime) in humans is only about 50%. (Borin MT., et al 1999). The low bioavailability of CP is mainly attributed to the degradation of its ester side chain by cholinesterase present in the intestinal lumen before absorption in addition poor aqueous solubility (400μg/ml), may also be responsible for its poor bioavailability which makes dissolution as a rate-limiting factor in intestinal absorption of poorly water aqueous drug CP (Kakumanu, VK, et al 2006). SDs is one of the valuable techniques to improve the solubility (Chiou, WL., et al., 1971) by using different hydrophilic polymers either by reducing drug particle size to the absolute minimum (micronization) thereby enhancing the drug wettability followed by notable improvement in bioavailability (Vasconcelos T et al., 2007). They are usually presented as amorphous products, mainly obtained by two major different methods, for example, melting and solvent evaporation (Fahr A et al., 2007) (Majerik V., et al., 2007).

 

 

Table I: Formulation table of CP by solid dispersion and co-grinding method

(SD=Solid dispersion, CG=Co- grinding mixture, PEG=Polyethylene glycol, PVP=Polyvinyl pyrrolidine, SSG=Sodium starch glycolate, CCS= Croscarmellose sodium)

 

Table II: Formulation table of CP by physical mixture method

(PM=Physical mixture, CG=Co-grinding mixture, PEG=Polyethylene glycol, PVP=Polyvinyl pyrrolidine, SSG=Sodium starch glycolate, CCS=Croscarmellose sodium)

 

 

 

2. MATERIALS AND METHODS:

2.1 Materials

The drug cefpodoxime proxetil was obtained as a gift sample from RA Chem, Hyderabad.  All other excipients and chemicals used are of laboratory grade.

 

2.2 Physical mixture of CP with carriers such as PEG 6000, PVP K30, CCS, SSG and polyplasdone XL in 1:2, 1:3 and 1:4 ratios

The physical mixture (PMs) were prepared by weighing required amounts of the drug and the carrier, followed by geometrically mixed (previously screened through 40#) for 20 min in the glass mortar. PMs were prepared for each drug: carrier ratios for further evaluation and were coded as shown in table 2. (Bahl, M et al., 2008).

 

2.3 Solid Dispersion of CP with PEG 6000 in 1:2, 1:3 and 1:4 ratios by fusion method

The solid dispersion of CP with PEG 6000 was prepared by using fusion method in 1:1, 1:2 and 1:4 ratios. PEG6000 was melted at 60-65⁰ C in pre-heated china dish on water bath. Then the CP was added in to molten PEG 6000 with stirring and then obtained mass is cooled to room temperature and dried (Leuner, C et al., 2000). The prepared solid dispersion was pulverized using glass mortar and sieved through 40#. The solid systems were coded as SD-1, SD-2 and SD-3 (Solid dispersion of CP: PEG 6000 in 1:1, 1:2 and 1:4 ratios).

 

2.4 Solid Dispersion of CP with PVP K30 in 1:2, 1:3 and 1:4 ratios by Using Solvent Evaporation Method

The solid dispersion of CP with PVP K30 were prepared using solvent evaporation method in 1:1, 1:2 and 1:4 ratios, by dissolving accurately weighed amount of PVP K 30 and drug in beaker containing methanol with the aid of heating at 70⁰C in a water bath for evaporation of solvents (Serajuddin, AT., 1999). The obtained solid dispersion were powdered in a mortar and passed through 40#. The solid dispersion was coded as SD-4, SD-5 and SD-6 (Solid dispersion of CP: PVP K 30 in 1:1, 1:2 and 1:4 ratios) as show in table 1.

2.5 Physical mixture of CP with SSG, CCS and Polyplasdone XL by co-grinding using ball mill in 1:2, 1:3 and 1:4 ratios

The cefpodoxime proxetil pure drug alone and in combination of drug and carriers namely SSG, CCS and polyplasdone XL were mixed and placed into the ball mill chamber by varying concentration of drug and carrier ratios (1:1, 1:2, 1:4) such that all formulation containing 10g of drug and carrier (Balasubramaniam, J et al., 2009)( Sugimoto, M. et al., 1998). Eighty five metal balls with three different diameters (9mm, 14mm, and 18mm) were added in the ball mill chamber so that the total volume of powder mixture and balls equaled about 1/3^rd volume of the ball mill chamber (Otsuka, M et al., 1998). The powder mixture was then grounded at 72 rotations per minutes for 2hrs, after grinding the sample were collected, stored and labelled as CG-7, CG-8 and CG-9 for  sodium starch glycolate with different ratios of 1:1, 1:2 and 1: 4 and CG-10, CG-11 and CG-12 for CCS with different ratios of 1:1, 1:2 and 1:4 and CG-13, CG-14 and CG-15 for polyplasdone XL with different ratios of 1:1, 1:2 and 1:4 (Fassihi, AR., et al 1985)( Mura, P. et al., 2009)( Shin, SC., et al, 1998).

 

Table III: Estimation of Drug content

S. No	Formulation code	%Drug content
1	SD l	90.52
2	SD 2	104.47
3	SD 3	103.42
4	SD 4	101.05
5	SD 5	99.73
6	SD 6	98.15
7	CG 7	93.15
8	CG 8	95.00
9	CG 9	102.36
10	CG 10	91.57
11	CG 11	101.84
12	CG 12	102.36
13	CG 13	95.52
14	CG 14	97.10
15	CG 15	100.52

(Data represents as n=3, SD= solid dispersion, CG= physical mixture)

 

3. EVALUATION:

3.1Estimation of drug content

Solid dispersion and co-grinding mixture of equivalent to 100mg of cefpodoxime proxetil were weighed accurately and dissolved in 100ml of methanol and kept in a bath sonicator for 20mts. The sample were further diluted with methanol and analyzed for drug content using UV-spectrophotometer at 259nm against methanol as a blank.

 

3.2 Characterization

The characterization of solid dispersion and co-ground mixtures were done by using FT-IR spectroscopy studies (Shelto CT, USA) and differential scanning calorimetry (Mettler DSC 823e, Mettler-toledo, Germany) to observe the physiochemical interaction between drug and excipients (Vogt, M., et al 2008). The powder X-ray diffraction studies (PW 1050/PW 1710) were used to study the crystalline behaviour and scanning electron microscopic(S-4100, Hitachi, Japan) observation was performed to study the morphological behaviour of solid dispersion and co-grinding mixture with comparison to the pure drug.

 

3.3 In-vitro dissolution studies

The dissolution rate studies  of cefpodoxime proxetil alone, grinded drug, solid dispersions, co-grinding mixtures and physical mixture were performed in triplicate in a dissolution apparatus (Lab India, DS 8000, Mumbai, India) using the paddle method(USP Type II). Dissolution studies were carried out using 900ml of glycine buffer (pH 3+0.1) at 37+0.5⁰C at 75rpm. 100mg of drug or its equivalent amount of solid dispersions, co-ground mixture and physical mixture were added to 900ml of glycine buffer (pH 3+0.1) as per USP. Samples of 5mL were withdrawn at time intervals of 5, 10, 15, 20, 25, 30, 40, 50 and 60min. the volume of dissolution medium was adjusted to 900ml by replacing each 5mL aliquot withdrawn with 5ml of fresh glycine buffer (pH 3+0.1). The samples were further diluted and the concentrations of drug in sample were determined using UV- spectrophotometer at 259nm against glycine buffer (pH 3+0.1) as a blank. The percentage cumulative drug release with respect to time was calculated using regression equation generated from the standard graph data (Yamada, T et al., et al 1999).

 

4. RESULTS AND DISCUSSION:

4.1 Estimation of drug content

The determination of the Drug content, indicated that the CP is uniformly distributed in all solid dispersions were as in co-grinding and physical mixture the variation in the drug concentration is observed with respect to the formulation process. The amount of drug incorporated in all the formulated batches is in the range of 90% to 104%.

 

4.2 Characterization

4.3 FTIR studies

To characterize the possible interaction between drug and polymeric carrier in solid state, IR-spectra have been studied and it concludes that there is no significant physiochemical interaction between the drug and the polymeric functional groups were shown in figure.5 (g).

 

 

 

Table IV: Cumulative percent drug release of formulation with PEG6000 and PVP K30

Time in min	% Cumulative drug release formulation with PEG6000							% Cumulative drug release formulation with PVP K30
	Drug	SD1	SD2	SD3	PM1	PM2	PM3		SD4	SD5	SD6	PM4	PM5	PM6
0	0	0	0	0	0	0	0		0	0	0	0	0	0
5	3.04	18.77	13.03	33.63	10.11	15.30	22.76		29.05	23.20	40.61	8.40	9.90	17.06
10	7.05	24.96	30.61	38.54	15.37	20.57	30.21		45.33	35.79	67.90	17.06	15.44	24.01
15	10.21	35.56	41.97	44.26	19.86	26.0	36.12		57.03	55.11	79.41	21.96	25.33	29.54
20	15.48	37.21	48.52	50.80	24.38	29.49	37.05		66.04	64.23	83.56	27.09	28.30	34.59
25	18.78	41.53	58.96	59.34	27.60	33.03	41.58		71.07	69.95	90.13	27.93	30.9	36.41
30	23.98	47.70	70.89	67.53	30.66	35.14	49.09		77.82	83.01	92.59	30.86	33.94	38.97
40	31.12	58.20	75.76	77.54	34.77	39.92	57.88		80.15	87.76	97.46	34.46	36.48	40.85
50	35.34	63.62	81.87	88.38	37.84	50.79	63.29		86.10	92.32	100.17	36.36	39.25	52.85
60	40.07	66.49	91.68	92.60	40.31	56.58	66.59		86.78	95.83	100.05	41.32	43.62	56.07

SD= solid dispersion, , PM=physical mixtures, PVP= polyvinylpyrrolidine, PEG= polyethylene glycol

 

Table V: Cumulative percent drug release of formulation with SSG and CCS

Time in min	% Cumulative drug release formulation with SSG								% Cumulative drug release formulation with CCS
	Drug	GRDR	CG7	CG8	CG9	PM7	PM8	PM9	CG10	CG11	CG12	PM10	PM11	PM12
0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
5	3.04	1.67	12.54	8.30	12.66	5.96	6.30	11.91	28.78	25.25	44.38	10.37	15.47	10.97
10	7.05	3.85	20.75	17.69	21.66	8.35	13.19	18.97	50.23	34.44	60.33	13.56	55.63	19.99
15	10.21	8.17	28.24	26.92	29.47	14.18	18.75	25.89	61.98	48.73	70.08	20.06	28.67	25.33
20	15.48	12.76	32.92	32.98	34.05	17.30	22.41	30.40	69.57	55.94	73.19	24.59	32.90	32.24
25	18.78	17.59	35.82	39.23	36.25	20.74	25.62	34.25	72.06	73.71	80.29	29.05	34.49	35.55
30	23.98	22.70	37.89	40.28	38.42	24.32	32.10	38.0	74.09	83.37	84.50	33.54	37.60	40.37
40	31.12	34.42	39.08	55.79	62.43	29.43	35.07	43.90	77.54	88.25	91.03	38.31	42.47	54.04
50	35.34	42.19	40.53	68.45	73.40	34.47	37.96	48.39	80.53	91.25	95.71	41.22	52.03	61.58
60	40.07	46.65	41.46	76.23	77.11	40.19	41.08	51.18	82.37	97.64	98.95	46.20	58.25	67.01

GR DR= ground drug, CG= co-ground mixture, PM=physical mixtures, CCS=Croscarmellose sodium, SSG= sodium starch glycolate.

 

Fig. I: Cumulative percent drug release of formulation with PEG6000 and PVP K30

 

Fig. II: Cumulative percent drug release of formulation with SSG and CCS

 

Fig. III: Cumulative percent drug release of formulation with Polyplasdone XL

 

 

Fig. IV: Cumulative percent drug releases of best formulations

 

Table VI: Cumulative percent drug release of formulation with Polyplasdone XL

GR DR= ground drug, CG= co-ground mixture, PM=physical mixtures

 

 

4.4 Differential scanning calorimeter

Differential scanning calorimetry enables the quantitative detection of all process in which energy is required or produced (i.e. endothermic and exothermic phase transformations) DSC curves obtained for pure CP, PVP K 30, CCS solid dispersion with PVPK30 (SD6) and co-grinding mixture with CCS were shown in figure.6.    Pure CP showed a melting endotherm at 99.0⁰C with enthalpy of fusion (ΔH) 4.206J/g) in figure no.6 (a). DSC scan of PVP showed a broad endotherm of melting point 68.7⁰C with ΔH 9.19J/g and the broad peak indicates the presence of the residual moisture in PVP in figure no.6 (b), whereas CCS also showed a broad endotherm of melting point 66.9⁰C with ΔH is 14.36J/g and broad peak indicates moisture content in CCS in figure no 6(c). The thermogram of solid dispersion of PVP K 30 with CP showed the melting point of 81.1⁰C of  ΔH 17.85 J/g and there is an observable shift in the melting peak for drug, it indicates the interaction between the drug and PVP K30 results the formation of solid dispersion in figure no. 6(d). The change in the value of ΔH also indicates the formation of a solid dispersion. The broad range of peak in the solid dispersion indicates the loss of water due to the extremely hygroscopic nature PVP polymer.

 

     Fig. VI (a): DSC thermo gram of pure CP                                                          Fig. VI (b): DSC thermo gram of PVP K30                  

 

   ig. VI(c): DSC thermo gram of CCS                                                                       Fig. VI (d): DSC thermo gram of CP-PVP K30 SD         

                                         

Fig. VI (e): DSC thermo gram of CP-CCS at 1: 4 ratio (CG12)

 

Fig. VII: SEM images of drug (A, B), grounded drug (C, D), SD6 (E, F) and CG 12 (G, H)    

 

 

The DSC curve obtained for co-grinding mixture of CP with CCS indicates disappearance of melting peak of drug and presence of broad peak with melting point of 64.4 ⁰C of ΔH 6.24J/g, it indicates the miscibility of drug in the CCS, and the reduction of ΔH results the reduction of particle size of the drug, increased surface area and decreased enthalpy of fusion (ΔH) when it compared with pure drug in figure no 6(e).

 

4.5 Scanning electron microscopy

SEM technique that can provide information about the morphology and particle size of pure compounds and as well as solid dispersion and co-grinding mixtures. The SEM of pure CP, grounded CP, and Solid dispersion with PVP K 30 (SD6) and co-grinding drug with CCS (CG12) were shown in figure no.7. The un-grounded CP has appeared as small, amorphous particles with rough surface and having particle size below 10µm. and also the grounded CP has appeared as small, amorphous particles with rough surface, having particle size below 10 µm, but it is observed that aggregation of fine particles which is due to its decreased particle size and increased surface tension which results in increased cohesive forces.

 

The solid dispersion of drug and PVP K30 (SD6) appeared as small particles with smooth surfaces, having particle size ranging from  10-100µm and original morphology of drug could not be detected, it indicates the miscibility of the drug in the carrier. The thin layer wrinkles on the smooth surface of solid dispersion are one of the surface characteristic that would form during evaporation of solvents from solid dispersion of drug PVP system. The co-grinding mixture of drug with CCS appeared as small needle like crystalline particles with rough surfaces, (this property is due to CCS, because it is not observed in morphology of pure drug) having particle size ranges from length 50-100 µm and width 10-30 µm, and fine drug particles are homogeneously dispersed on to the carries. In co-grinding mixture (CG12), the rough surface, needle like crystalline particles were observed, which is in good agreement with XRD data. (Appearance of distinct crystalline peak pattern in CG12)

 

4.6 X-ray Diffraction (XRD) analysis

The XRD study is carried out to characterize the physical form of the drug and the carrier presence in the formulation. The XRD pattern of pure CP and grounded CP in figure no. 8&9 and the XRD pattern of the drug and the grounded drug indicates the complete lack of peaks and a halo pattern, typical of amorphous material and a broad hump is visible between 17⁰ and 25⁰ of diffraction angle 2θ. These results are best agreements with the previous investigations preformed by Voinovich et al. The difference between the drug and grounded drug is the crystalline intensity of the baseline is lower to the grounded drug than the pure drug of CP. The XRD pattern of optimized formulations SD6 (solid dispersion with PVP K30) and CG12 (Co-grinding mixture of CP and CCS) are shown in figure no.10 & 11. The XRD pattern of solid dispersion with PVP K30 in a ratio of 1:4 (SD6) indicates the solid dispersion product present in amorphous powder having no crystalline peaks and a broad hump between 17⁰ and 25⁰ of 2θwhich relates to CP. The X-ray diffractogram of CG12 has sharp peaks at diffraction angle (2θ) 19.01⁰, 26.63, 28.01, 29.39, 33.10, 33.82, 45.42, 48.77, 56.46 and a broad hump between the 18⁰ and 25⁰ of 2θ. All the crystalline peaks appeared in the diffractogram are related to carrier present in co-grinding mixture but not of the drug, (because the drug in amorphous form which have no crystalline peaks in its X-ray diffractogram) and broad hump which is present between 18⁰ and 25⁰ of 2θ is relates to drug in the co-grinding mixture.

 

4.7 In-vitro dissolution studies

The dissolution studies were carried out in triplicate and the results were presented as mean values, the error bars represent the standard deviation (SD). The rates of dissolution of all the formulated batches are compared with that of the pure drug. Dissolution study of drug with PEG 6000 is studied and shown in table.4 and figure.1. The solid dispersion and co-grinding mixture were exhibited a significant increase in dissolution rates than the pure drug. The increased excipient ratios were increases the dissolution rate of the drug.

 

Table VII: Cumulative percent drug releases of best two formulations

 

 

Table VIII: Summary of dissolution parameters for solid dispersion and co-ground mixtures

FORMULATION	DISSOLUTION PARAMETERS
	Q15	DE15	MDT(Min)	/1	.12
Pure drug	10.213	5.065	27.122	-	-
Un grounded Drug	8.173	3.201	30.205	2.596	72.341
S0 l	35.557	20.504	19.416	53.034	32.538
S0 2	41.974	21.541	21.476	63.945	21.830
SD 3	44.261	31.435	19.378	66.511	20.169
SD 4	57.030	34.298	13.644	69.123	17.647
SD 5	55.114	28.852	16.756	69.522	16.794
SD 6	79.410	49.404	10.237	75.386	10.932
C0 7	28.236	15.803	13.229	36.013	45.719
C0 8	26.919	13.148	26.531	49.415	33.859
C0 9	29.475	16.316	24.958	51.975	31.824
CO 10	61.977	36.668	11.907	69.009	17.766
CO 11	48.725	28.016	18.021	69.082	17.147
CO l2	70.083	46.584	13.134	73.504	13.214
CO 13	8.493	2.864	31.206	18.417	70.270
CO 14	9.293	3.022	28.604	5.324	90.043
CO 15	18.697	7.830	24.989	30.792	50.630

(Data represents as n=3, Q 15= percentage drug dissolved at 15min, DE= dissolution efficiency, MDT= mean dissolution time,  I= dissimilarity factor, j,= similarity factor)

 

Table IX: Summary of dissolution parameters for physical mixtures

 

(Data represents as n=3, Q 15= percentage drug dissolved at 15min, DE= dissolution efficiency, MDT= mean dissolution time, I= dissimilarity factor, j= similarity factor)

 

The dissolution rate drug from the solid dispersion and co-grinding mixture is depended on drug excipient ratio. As the proportion of excipients in solid dispersion and co-grinding mixture is increased, the dissolution rate has also been increased. The solid dispersion and co-grinding mixture with 1:4 ratios of drug and carrier exhibited higher dissolution rate than the others with lesser carries content (1:1 and 1:2). The order of dissolution shown by the solid dispersion and co-grinding mixture is found to be 1:4>1:2>1:1. The rank order of dissolution rate enhancement of different carries is in the order of PVPK 30M> CCS> PEG 6000> SSG> Polyplasdone. The solid dispersion SD6 and co-grinding mixture CG12 had showed marked enhancement in the dissolution rate of the drug (up to Q15=79.46% for SD6, Q15= 70.08% for CG12) than all other formulations. Thus the SD6 and CG12 are selected as the best formulation among the all other groups and dissolution studies are compared with intact drug and grounded drug.

 

4.8 Model Independent parameters

The percentage drug dissolved in 15 min (Q15), dissolution efficiency at 15min (DE15), Mean dissolution time (MDT), dissimilarity factor (F1), and similarity factor (F2) has been summarised in table 8 and 9. In order to have better comparison between physical mixtures, solid dispersion and co-grinding mixtures, independent dissolution parameters such as DE and MDT were calculated.

 

4.8.1 Dissolution efficiency

The  dissolution efficacy of pure drug showed  at the end of 15 min was 10.21% (Q15) drug release were as for ground drug showed 8.17% (Q15) drug release, and the highest dissolution rate  is exhibited by SD6 (Q15= 79.41%) and CG12 (Q15=70.08%). The dissolution efficiency of pure drug at 15min is 5.065 and it is increased to 49.404 in SD6 and 46.584 in CG12 formulations among the all other formulations. The grounded drug showed dissolution efficiency low at initial time but it is increased slightly at time 60min in solid dispersion and co-grinding mixtures Q15 and DE% increases with increase in ratio of carrier. The Q15 and DE% were increased in the carriers PVP and Croscarmellose sodium at highest drug carrier ratio than other carries.

 

4.8.2 Mean dissolution

The mean dissolution time for pure cefpodoxime proxetil is 27.122 while minimum MDT is seen in SD6 is 10.237 and CG12 is 13.134. The minimum MDT is indicates the better dissolution Rate.

 

4.8.3 Similarity (f2) and Dissimilarity factors (f1):

Similarity factor (F2) and Dissimilarity factors (f1) were calculated to compare the dissolution profile between untreated cefpodoxime proxetil and its corresponding formulation. A value of hundred for f2 and zero for F1 suggest that the test and reference sample were identical. Generally, f1 values up to 15(0-15) and f2 values greater than 50(50-100) ensure the sameness or equivalents of dissolution profile.  In all formulations the dissimilarity factors f2 increases and similarity factor f1 decreases with respect to drug carrier ratio. The formulation SD6 and CG 12 shown the F1, F2 values are 75.386, 10.932 and 73.504, 13.214 respectively. These formulation were shown high dissimilarity and low similarity factor values among all other formulation with compare to pure drug that indicated there have dissolution profiles were different from the dissolution profile of the pure drug. It conclude that poor dissolution rate of cefpodoxime proxetil differ to high dissolution rate of SD6, CG12.  The solid dispersion SD6 and co-grinding mixture CG12 have showed marked enhancement in the dissolution rates of CP (up to Q15= 79.46% for SD6 , Q15 = 70.08% for CG 12), high dissolution efficiency (DE15%= 49.404 for SD6 and DE 15%= 46.584 for CG12) and low mean dissolution time( MDT=10.237 for SD6 and MDT = 13.134 for CG12), than the all other formulation ,thus the SD6 and CG 12 were selected as the best formulation among the all other CP formulation. These formulations were further subject to characterization of the physicochemical interaction between the drug and the carrier using FT-IR spectroscopy, DSC and X-ray infraction and SEM studies.

 

4.9 In-vitro drug release kinetics

In-vitro release of best formulation of CP (CD6, CG12) is carried out. The correlation co-efficient (r²) values are of first order kinetics 0.9948 and 0.9946 and r² value for zero order kinetics 0.636 and 0.7155 respectively for optimized formulation. R² value of first order release kinetics is more nearer to 1 than the r² value of zero order kinetics models. Which results in the optimized formulation follows the first order kinetics that the drug release of the solid dispersion and co-grinding mixture is depend upon its concentration. The results are in agreement with previous investigation performed by kamal dua et al, Sivakumar et al and Ei maradny et al. The regression co-efficiency values of kinetic model were optimized formulation were shown in table.8 and 9. The data were further subjected to higuchi equation, and Hixson coxwell cube root law. The higher correlation as indicated by r² were observed for Hixson crowel release in the optimized formulation suggesting the release rate is limited by drug particle dissolution. Here the drug is released by diminishing of the particle size undergoes reduction. The formulation follows the first order kinetic and the rate release limited by particle size diameter and surface area because the drug released by the reduction of particle size. The formulation CG12 also follows majorly first order kinetics. Hixson crowel drug release along with higuchi release kinetics suggesting diffusion also probable mechanism of drug release along with drug particle dissolution.

 

5. SUMMARY AND CONCLUSION:

The solubility and dissolution rate of CP in tablet dosage form can be enhanced by use of solid dispersion of CP with PVP K30 in ratio of 1:4 and by co-grinding of drug with CCS in ratio 1:4, showed better dissolution rate compared to the pure drug and other formulations. The solubilization effect of PVP K30 and CCS, reduction of particle aggregation of the drug, absence of crystallinity and alteration of the surface properties of the drug particles might be responsible for the enhanced solubility and dissolution rate of CP from its solid dispersion and co-grinded mixture. From FTIR spectroscopy, it was concluded that there was no well defined interaction between drug and carrier, since no peaks of shift of peak could be observed. The shift in the endothermic peak of CP in the DSC thermo grams showed the formation of solid dispersion and co-grinded mixture with amorphous state. In addition, XRD and SEM studies supported the conclusion drawn from the DSC study. It can be concluded that the preparation solid dispersion and co-grinded mixture of Cp with PVP K30 and CCS provides a promising way to enhance its solubility and dissolution rate.  

 

6. REFERENCES:

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Received on 15.10.2012          Modified on 20.10.2012

Accepted on 06.11.2012         © RJPT All right reserved