Formulation and Development of Sustained Release Microspheres of Metformin Hydrochloride


Parag N Bhangale*1, Hitendra S Mahajan and Rajendra D Wagh1

1A.R.Ajmera College of Pharmacy, Dhule -424005

2 R.C. Patel Institute of Pharmaceutical Education and Research Shirpur, Dist Dhule- 425405

*Corresponding Author E-mail:



Metformin hydrochloride microspheres were prepared by non-aqueous emulsification solvent evaporation method, using hydrophobic polymer i.e. ethyl cellulose and hydroxy propyl methyl cellulose K15M. Spherical microspheres having an entrapment efficiency of 80% - 87% and percentage yield of 71% - 90% were obtained. The effect of polymer-drug ratio, stirring speed was evaluated with respect to entrapment efficiency 80% -87% and percent yield 71% - 90% was obtained. The effect of polymer- drug ratio, stirring speed was evaluated with respect to entrapment efficiency, percentage yield and in vitro drug release behavior. Visual inspection and infrared spectroscopic analysis confirmed the absence of drug-polymer interaction. Te in vitro release profile could be altered significantly by changing the drug to polymers ratio to give sustained release of drug from microspheres. The F2 factor was found to 74 % compared with marketed sample. The optimized formulation M8 was kept for stability study at refrigeration temperature, room temperature and at oven temperature (40o C to 45o C) showed no significant drug interaction.







Microspheres are solid, approximately spherical particles ranging 1-1000 µm in size which can be efficiently used for sustained release of drugs. It is used to modify or retard the drug release. Diabetes is one of the major causes of death in the world. Various antidiabetic drugs are used in clinic, of which Metformin hydrochloride is very widely accepted drug. Unlike other antidiabetics Metformin hydrochloride does not induce hypoglycemia at any reasonable dose and hence? It is usually called an antihyperglycemic rather than a hypoglycemic drug. In spite of its favorable clinical response and lack of significant draw backs, chronic therapy with Metformin suffers from some certain specific problems of which, the most prominent being the high dose(1.5-2g/day), low bioavailability (60%), and high incidence of GI side effects (30%), no plasma binding and high renal clearance. Therefore, there are continued efforts to improve the pharmaceutical formulation of Metformin hydrochloride in order to achieve an optimal therapy. These efforts mainly focus on controlled/slow release of drug. It was found that reduction of total administered dose reduces the severity of the toxicity. Thus the half life of 1.5 – 3hrs and lower bioavailability makes the Metformin hydrochloride a good candidate for sustained release.


Microspheres provide the prolonged release of drug, thereby minimizing the frequent administration and elicit pharmacological activity, which reduces the side effects. A combination of hydrophobic polymer ethyl cellulose and hydrophilic polymer hydroxy propyl methylcellulose K15M is used to retard the highly water soluble drug Metformin hydrochloride. A combination is used because it is very difficult to retard the release of highly water soluble drug having water solubility >354 mg/ml. with hydrophilic polymer HPMC K15M so to achieve  a good slower release a hydrophobic polymer is used in  combination. A non-aqueous solvent evaporation method is used to prepare microspheres of Metformin hydrochloride. Several researchers have investigated the utilization of ethyl cellulose as a polymer to microencapsulate drugs by coacervation separation technique, Emulation solvent evaporation technique, and spherical crystallization technique.


The purpose of the present study was to prepare and evaluate orally sustained release microparticulate drug delivery system of Metformin hydrochloride, by using combination of the ethyl cellulose and HPMC K15M polymers by using non-aqueous emulsification solvent evaporation technique. Various process parameters such as drug-polymer ratio, stirring speed, and volume of processing medium were optimized to maximize entrapment efficiency. These microspheres were evaluated for the drug content and in vitro drug release.  Drug- polymer interactions were in the solid state studied by infrared spectrophotometry (IR).  The surface characteristics were evaluated by scanning electron microscope (SEM).1-4.                  



Metformin was received as a gift sample from G. Amphary laboratories. Ethyl cellulose (14 Cps viscosity grade, apex chemicals, Mumbai), dichloromethane (loba-chem. Pune), liquid paraffin (cosmo chem. Pune), petroleum ether (loba chem. Pune). All the reagents andsolvents used were of analytical grade, satisfying pharmacopoeial standards.


Preparation of microspheres: 5,6.    

The polymer ethyl cellulose and hydroxyl propyl methyl cellulose was dissolved in the mixture of ethanol and dichloromethane (1:1). The drug Metformin Hydrochloride was dispersed in solution for 10 minutes under stirring at 200 rpm. The resulting dispersion was poured slowly under stirring into liquid paraffin (dispersion medium) containing 0.01% of tween 80 and  the stirring speed was maintained at 600 rpm with gentle heating by means of heating plate at about 450C-500C and stirring was continued for 2 to 5 hrs and allow to evaporate dichloromethane and ethanol completely.  After evaporation of dichloromethane and ethanol, the microspheres formed were collected by filtration under vacuum, and then washed 3 to 4 times with petroleum ether. After the microspheres are washed 2 times with distilled water and dried at room temperature for 24 hrs. A mechanical stirrer (Mechanical stirrer, REMI, India) with a blade of 3.5 cm diameter were used. The formulation batches were prepared with different ratios of drug to polymer and keeping all other parameter constant.


Fig No.1 comparison of percent yield and DEE of microspheres.


Evaluation of microspheres

Entrapment efficiency7-9.

To determine entrapment efficiency, 100mg accurately weighted microspheres were crushed and dissolved in a minimal amount of mixture of dichloromethane and ethanol (10ml) in a volumetric flask, shake it for 15 min. and the volume was adjusted up to 25ml with phosphate buffer pH 6.8  solution. The microspheres were kept to soak for overnight. After 12hrs the solution was filtered through 0.45m membrane filter. The volume was made up to 25ml with phosphate buffer pH 6.8 and analyzed for drug content spetrophotometrically at 232 nm. Corresponding drug concentrations in samples was calculated from calibration plot. The results are shown in fig no.1.


                                  Estimated % drug content in microsphere x 100

Entrapment efficiency = --------------------------------------------------------

                                    Theoretical % Drug content microsphere


Percent yield:

The percentage yield value is defined as the quantity of beads produced as a function of loaded drug and polymer. The results are shown in fig no.1.



                                 Weight of microsphere x 100

Percent yield  = --------------------------------------------------------

                                Total weight of Drug  and polymer taken




Size distribution and size analysis of microspheres10-12.

Size distribution of Metformin hydrochloride microspheres was studied by optical microscopic analysis. The average particle size was determined by using Edmondsons equation D= nd/n. where n= number of particles. The surface topology study was done by SEM analysis study at different magnification.


Micromeretic properties12-14,:

Bulk density and tap density of the prepared microspheres were determined. Carr’s index and hausner’s ratio was calculated. Angle of repose was assessed to know the flowability of microspheres by fixed funnel method.


Scanning electron microscopy15,16.:

SEM was taken using scanning electron microscope model JSM-6390, Japan, at suitable magnification. The photographs were observed for morphological characteristics and to confirm spherical nature of microspheres. The results are shown in fig. no. 2 and 3.


Fig .no.2. SEM photograph of Metformin Hydrochloride HCL microspheres M82

Table No. 1.Formulation batches of microspheres of Metformin hydrochloride.

Sr. No.

Formulation code

Drug: EC:HPMC K15M (  gm)

Solvent ratio Ethanol: DCM (ml)

Tween 80 (%)












































































Fig .no.3.SEM photograph of Metformin Hydrochloride HCL microspheres M8-2


Differential scanning calorimetry (DSC)17,18:

DSC was use to determine a shift of ethyl cellulose and HPMC endothermic peak or the appearance of exothermic peaks and consequently detect interaction between Metformin Hydrochloride and ethyl cellulose and HPMC. DSC thermograms of empty microspheres, pure drug and microspheres with drug were determined. Absence of any new endothermic peak or disappearance of no shift of endothermic peak confirms that there is no any interaction and hence the polymer compatible with drug.99,57. The results are shown in fig. no. 4 and 5. DSC of pure drug.


Fig no.5. DSC of stability batch M8-3


The XRD studies have revealed that there is no drug interaction between drug and excipients during stability.


X-ray diffraction study19,20.:

Power X-ray diffraction patterns were obtained using an X-ray diffractometer at 30 mA and 40 kV. The instrument is operated in step scan mode from 10.540 to 27.230.X-ray diffraction of Metformin Hydrochloride +ethyl cellulose +HPMC for optimized batches was carried out. And the X-ray diffraction of ethyl cellulose and HPMC was carried out. The results are sown in fig. no. 6 and 7.


Fig. No.6. X-RD of blank microspheres.


Fig. No.7. X-RD of batch M8-3


In vitro studies:5,21.:

A USP basket apparatus has been used to study in vitro drug release from microspheres.48 In vitro drug release studies were carried out for all batches in USP type II [DISSO 2000, Labin, India] dissolution test apparatus at 100rpm and the dissolution medium used is 900ml of phosphate buffer pH 6.8.28 Microspheres containing 500 mg of drug was used for dissolution study. Five ml of the aliquot was withdrawn at predetermined intervals .The required dilutions were made with 6.8 Ph phosphate buffer and filter the solution and analyzed for the drug content spetrophotometrically (UV 1800, Shimadzu, Japan) at 232nm against suitable blank. Equal volume of the dissolution medium was replaced in the vessel after each withdrawal to maintain sink condition. From this percentage drug release was calculated and plotted against function of time to study the pattern of drug release. The similarity of dissolution profile of the prepared formulations was compared with that of the marketed formulations to arrive at the optimum profile. Similarity factor (f2 value) was calculated as follows: f2 = 50 log {[1+1/nΣ (Rt – Tt)2]-0.5 × 100} by using PCP disso software, Where, Rt and Tt are percent of drug which was dissolved at each time point for the test and reference products respectively, n is the number of time points considered. Results are shown in fig. no. 8.


Fig. no. 8.  Dissolution profile of various batches of Metformin HCL Microspheres

Stability study22. 

Stability study was carried out on the optimized formulation. The formulation was wrapped in the alluminium foil and then placed in the glass bottle. It was stiored at room temperature, at 40 to 45 C and at refrigeration temperature for a period of 3 months. The results obtained for zero time at room temperature, at 40 to 45 C and at refrigeration temperature.



Metformin hydrochloride due to its hydrophilicity is likely to preferentially partition out into the aqueous medium, leading to low entrapment efficiency, when encapsulated using aqueous phase as the processing medium. In this study attempt was made to encapsulate Metformin hydrochloride with sufficiently high entrapment efficiency by non-aqueous emulsification solvent evaporation method using a non-aqueous processing medium. The primary requirement of this method to obtain microspheres is that the selected solvent system for polymer be immiscible with non-aqueous processing medium. Mixture of ethanol and dichloromethane was used as medium to solubilize both polymer ethyl cellulose and HPMC because both polymers are soluble in mixture of ethanol and dichloromethane. A surfactant system tween 80 is used to emulsification of polymer and drug to form the microspheres. It has HLB value of 4.3 and is expected to have a high disparity for the present emulsion system by reducing the surface tension at the interface. The optimal proportion of ethanol and dichloromethane was found to be 1:1, which enabled emulsion formation and yielded good microspheres.


The compatibility of Metformin hydrochloride in ethyl cellulose and HPMC K15M was evaluated through IR spectroscopy, UV spectroscopy. The UV spectra of pure drug solution and the dissolution medium after drug release study were identical and the characteristics λmax of pure Metformin hydrochloride was appeared at 232 nm on the UV spectra of the dissolution medium after drug release study. It indicates no drug- polymer interaction. This was further confirmed by IR spectroscopy. The study of IR spectra of Metformin hydrochloride-loaded microspheres demonstrate that the characteristic absorption peaks for N-H bending was appeared at 1459 cm-1. The absorption peaks were almost similar to those obtained from the pure drug and to the reported value.


The surface topology of the microspheres was investigated by SEM. As seen in fig. no. 2and 3 they were spherical in shape. The SEM of drug-loaded microspheres in fig. no.2 has rough surface due to higher concentration of drug in the microspheres at high magnification. The particle size analysis of the prepared microspheres was evaluated by optical microscopic analysis. The particle size range of the prepared microspheres was found to be between 400 µm to 500 µm. It was found that the particle size of microspheres decrease with increasing the stirring speed of the stirrer. Particle size is also influenced by the ratio of both the polymer i.e. increasing the ratio of both polymer particle size also increases. At 600rpm stirring speed a satisfactory particle size was obtained.


The DSC curve of pure Metformin hydrochloride, Metformin HCL- loaded microspheres and blank microspheres are presented in fig no. 4 and 5 . It was evident from the DSC profile that Metformin HCL exhibit a sharp endothermic peak at 227oC which correspond to reported melting temperature of the drug. The same DSC profile of the drug appeared at the temperature corresponding to its melting point in the Metformin HCL-loaded ethyl cellulose and HPMC microspheres. The DSC profile of the blank microspheres did not exhibit endothermic peak at 227oC these studies revealed that the drug was compatible with the polymer and neither drug decomposition nor drug-polymer interaction occurred in the prepared microspheres.


Stability studies revealed that polymers used were stable and compatible with the drug and formulations were stable.


Metformin HCL in-vitro release from microspheres was studied in phosphate buffer pH 6.8 for periods of 10 hrs. The release pattern of microspheres was shown and spread over extended period of time. The Microspheres prepared with ratio of drug: Ethyl cellulose: HPMC K15M 1:0.5:0.625 shows good release pattern. The values of coefficient of correlation (r) were calculated and were found to be following the matrix order of release.



Sustained release microspheres were successfully prepared employing non-aqueous solvent evaporation technique. The method of preparation was found to be simple. The development strategy has shown that the stirring speed and ratio of polymers significantly affect the particle size, entrapment efficiency and drug release. From various trials it is shown that with increasing drug to polymer ratio there is an increase in entrapment efficiency and percent yield having maximum particle size. The parameters like particle size, entrapment efficiency and percent yield and drug release profile of all batches were evaluated and batch no M-8 shows satisfactory dissolution profile matching with the dissolution profile of marketed formulation.



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Received on 05.09.2009          Modified on 01.11.2009

Accepted on 10.12.2009         © RJPT All right reserved

Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 267-271