Studies on solid state compatibility of Vanlafaxine HCl with combination of HPMC and ionic polymers for extended release delivery

 

Bipul Nath¹*, Balen Saharia²

¹Royal School of Pharmacy, Assam Royal Global University, Betkuchi,

Guwahati-781035, Kamrup, Assam, India.

²Godrej Consumer and Products Limited, Guwahati, Assam.

 

ABSTRACT:

The objective of the present investigation is to detect interaction of Vanlafaxine HCl (VNF) and HPMC in combination with ionic polymers sodium alginate for extended release (ER) purpose by DSC and FT-IR method. In the first phase of the study, differential scanning calorimeter (DSC) was used as tool to detect any interaction. In the next phase, excipients defined in the prototype formula were tested for their compatibility with VNF using FT-IR. In this study it was possible to observe the interactions of the VNF with magnesium stearate and lactose. In brief, tablets of VNF having an average weight of 200mg were prepared using varying quantity of HPMC K4M and release studies were carried out in phosphate pH 7.4 for a period of 12 hour to achieve extended release pattern. The tablets were also evaluated for physical properties, kinetic studies and stability studies. FTIR and DSC studies shown there was no interaction between drug, HPMC K4M and other filler excipients. The physical properties of tablets were found within the limits. Formulation F-5 having a composition of 20.0% w/w HPMC K4M and 10% sodium alginate exhibit predetermine drug release up to 12 hours following diffusion controlled swelling and slow erosion. The optimized formulations were subjected to stability studies and shown there were no significant changes in hardness, drug content and in-vitro drug release behaviours. Results of the present study indicated the suitability of the HPMC K4M hydrophilic matrix polymers in the preparation of extended release formulation of VNF.

 

 

 

INTRODUCTION:

Extended release (ER) dosage forms are terms used to identify drug delivery system that are designed to achieve or prolonged therapeutic effect by continuously releasing medication over the extended period of time after administration of a single dose^[1,2]. The objective in designing an ER system is to deliver drug at a rate necessary to achieve and maintain a constant drug blood level. Techniques of thermal and isothermal stress testing (IST) were used to evaluate the compatibility of drug with selected excipients for the development of ER formulations.

 

The incompatibility between drugs and excipients can alter the physicochemical properties of drugs and hence, can have an effect on its efficacy and safety profile. Therefore, drug-excipient interaction study at the initial stage of a formulation development should be treated as an imperative exercise to ensure correct selection of excipients and hereby, increasing the possibility of developing a successful dosage form^[3,4]. In particular, the cost and time constraints associated with the process of pharmaceutical product development have made this type of predictability techniques even more desirable. As the thermo-analytical methods do not yield direct chemical information, Fourier transform infrared spectroscopic (FT-IR) investigations were also used in this work. The compatibility studies using thermal analysis present advantageous to readily available knowledge of any physical and chemical interactions between drugs and excipients which might give rise to changes in chemical nature, stability, solubility, absorption and therapeutic response of drugs^[5,6]. Thermal techniques have been increasingly used for quick evaluation of possible incompatibility between formulation components through comparison of thermal curves of pure substances with curve obtained from a 1:1 mixture.

 

Venlafaxine HCl (VNF) is a new generation antidepressant serotonin/noradrenalin reuptake inhibitor drug showing effective anti-depressant properties. It has a short oral bioavailability of 45% and biological half-life of 4-5 hours. The total daily dose of VNF is 225-375 mg/day in moderate and severe depressive disorder. So, frequent administration is necessary to maintain its therapeutic concentration. This necessitates of frequent administration of large doses (75mg every 4 to 5 h three times daily or four times daily) to maintain therapeutic drug level. The side effects of VNF are dose dependent and a reduction of the total administered dose reduces the severity of the toxicity. Thus the short half-life of 4 h and frequent dosing of large doses due to low oral bioavailability makes VNF a good candidate for ER.^[7,8] The aim of the present investigation was to study compatibility of VNF with selected matrix polymers and to prepare extended release tablets by direct compression method.

 

Combination of HPMC with ionic polymer has been reported to result in greater retardation in drug release profile compared to single polymer systems 12. In these formulations, rapid hydration of cationic gum combined with firm gel strength of HPMC have been attributed to the slower drug release of highly water-soluble APIs. In this system, the initial burst release, which is typical of highly soluble drugs, was controlled by rapid hydration of ionic polymer, whereas subsequent drug release and matrix integrity were maintained by the firm gel of HPMC.

 

MATERIAL AND METHODS:

Materials:

The VNF was obtained from Sigma Aldrich, Bangalore. Excipients tested were procured from certified vendors such as HPMC K4M (Loba chemie), sodium alginate, microcrystalline cellulose (Rankem), lactose (Lobachemie) and Stearic Acid, Magnesium stearate, PVP K30 from Loba chemie, Kolkata. The mixed samples consisted of equal masses of VNF and each excipient was weighed individually into amber glass bottles to originate mass of 2.0g of mixture. Physical mixtures were prepared in proportion 1:1 of VNF: excipient by simple mixing.

 

Methods:

Differential scanning calorimetry study:

A Mettler Toledo DSC thermal analysis system (Mettler Inc., Schwerzenbach, Switzerland) was used for thermal analysis of the drug-excipient mixtures. Approximately 2-5mg of VNF and excipient or their binary mixture was examined in the temperature range between 40^◦C and 300^◦C, in a normal covered aluminium pan (three pin holes were applied in the cover). The heating rate was 10ºC min^-1. Nitrogen was used as carrier gas at a flow rate of 10 Lh^-1 during the DSC investigation^[3,6].

 

Fourier transform infrared spectroscopy study:

FT-IR spectra of the VNF and its binary mixtures were recorded in the scanning interval of 400–4000 cm^-1 and optical resolution was set at 4 cm^-1 using a Schimadzu FT-IR instrument (Japan). Standard KBr pellets were prepared from analytical grade KBr using 0.5mg of VNF or 1.0mg of binary mixture. The spectra were recorded with the use of software, and all spectral interpretations were done^[3,12].

 

Preparation of Extended release tablet of VNF by direct compression:

The weighed quantity of VNF was screened through sieve no. #40. The various excipients were accurately weighed and screened separately using sieve no. #40. The extended release tablets were prepared by direct compression method using the formula shown in Table 1. Accurately weighed quantity of raw materials such as VNF, sodium alginate, PVP K30, MCC, HPMC K4M, Stearic Acid was sifted through sieve no. #40 and mixed them for 5 minutes. The blended drug-powder was compressed into tablets weighing approximately 200mg on a single punch tablet machine (Cadmach, Ahmadabad) using a flat-faced non-beveled punch and die set of 8-mm diameter^[10-12].

 

Evaluation of Pre compression Parameters:

It is very important parameter to be measured, since it affects the mass of uniformity of the dose. It is usually predicted in terms of angle of repose, bulk density and tapped density, compressibility index^[9,13].

 

Evaluation Post compression Parameters:

The formulated tablets were evaluated for the following parameters such as thickness, hardness, friability, weight variation and in-vitro drug release characteristics^[12,13].

 

In-vitro Drug Release studies:

Dissolution studies were carried out for all the formulations in USP Type II apparatus using 900ml of phosphate buffers (pH 7.4) as the dissolution medium. The medium was allowed to equilibrate to a temperature of 37°C±0.5°c. Each tablet was placed in the each chamber and stirring was continued for 12 hrs at 50rpm. At definite time intervals, 5ml of the aliquot sample was withdrawn periodically and the volume replaced with equal volume of fresh dissolution medium. The samples were analyzed spectrophotometrically at 274nm using UV spectrophotometer^[8,16]. The dissolution data was further fitted in to various kinetic equations to evaluate the drug release mechanism.

 

Kinetic evaluation of release data:

To evaluate the mechanism of drug release the drug release values were fitted in to various kinetic models such as zero-order, first order, Higuchi and Korsemeyer-Peppas^[17].

 

Zero-order

C = K_o.t ........................................................................(1)

K_o is zero order release constant and t is the time in hrs.

 

First-order

Log C = log Co – Kt /2.303..........................................(2)

 

Where C is the concentration, Co is the initial concentration of drug, K is the first-order rate constant, and t is the time.

Higuchi

Qt = K_H ·t^1/2 ..................................................................(3)

 

Where Q_t is the amount of release drug in time t, K is the kinetic constant and t is the time in hrs.

Korsmeyer peppas,

M_t / M_∞  = K · t ⁿ (4)

 

Where M_t represents amount of the released drug at time t, M_∞ is the overall amount of the total dose of drug. The value of n indicates the drug release mechanism related to the geometrical shape of the delivery system, if the exponent n = 0.5, then the drug release mechanism is Fickanian diffusion.  If n < 0.5 the mechanism is quasi-Fickian diffusion, and if the value lies between 0.5 and 1.0 (0.5 < n < 1.0), then it is non- Fickian or anamolous diffusion. When n = 1.0 the mechanism is non-Fickian case ІІ diffusion and if n > 1.0 the release mechanism is non-Fickian type or super transport case ІІ.

 

Stability studies:

The stability studies were performed by storing the optimized tablets at 40º ± 2ºC/75 ± 5% RH in stability chamber for 3 months. The samples were withdrawn in each one-month intervals up to 3 months and analyzed for various physical changes, drug content and extended release behaviour up to 12 hr.

 

RESULTS AND DISCUSSION:

Drug-excipient compatibility testing by DSC:

In the first phase the compatibility of VNF with different excipients was tested using DSC. Different formulation trials were selected to develop formulation compositions. The DSC thermogram of VNF (Figure 1) shows a sharp endotherm at 215.03°C with an onset of 211.45°C and the heat of fusion was found to be 124.41 J/g. The melting peak of VNF happened to 215.03°C followed by decomposition. The melting peak of VNF when disappeared, or decreased in intensity in drug-excipient binary mixtures, it was confirmed to be physical interaction. DSC curve of VNF+lactose shows characteristic immediate endothermic peaks of lactose with loss of water and a sharp endothermic peak at 207.5 °C, which got merged with the melting range of VNF indicating interactions. Such interactions of the binary mixture can be easily detected from the DSC curves and hence lactose was rejected from the formulation compositions. This fact is justified because the melting of drug and excipient occur in the same temperature range indicating solubility of drug in the excipient blends. The melting peak of VNF was retained in the binary mixture of sodium alginate, MCC, PVP K30, stearic acid respectively as shown in the Figure 1. The thermo-analytical data of DSC of VNF and drug-excipients mixtures were presented in Table 1.

 

Table 1. Thermoanalytical data of VNF and excipients 

 

However, in the binary mixture of VNF and magnesium stearate, the melting point of VNF was decreased of 215.83 to 207.08°C (T_onset of physical mixture). The corresponding data of VNF-magnesium stearate mixture indicate the occurrence of remarkable interaction, since the quantity of magnesium stearate employed in the tablet formulation would be very less (2 to 4%w/w). So, magnesium stearate was rejected from the formula and replaced with similar properties excipient stearic acid which shows compatibility as evident from the DSC studies.

 

Drug–excipient compatibility testing by FT-IR:

FT-IR analysis of the drug and their physical mixtures are shown in Figure 2. The characteristic peaks of VNF showed no change in its structure after mixing with polymers which confirmed the absence of any chemical interactions between the drug and polymers. The FT-IR study of pure drug showed principal peaks at 2942.78 cm^-1 and 1470.97 cm^-1 which appeared due to the presence of strong C-H stretching vibration of alkane and C-H bending of alkane respectively.

 

Figure 1. Comparative study of 1:1 binary mixtures of each drug and excipient by DSC

 

Peak observed at 768.88 cm^-1 showed characteristic peak due to C-Cl stretching of halogen group. O-H stretching of alcohol group was attributed to the peak appeared at 3318.48 cm^-1. While the C=C bending vibration of alkene was confirmed at 827.34 cm^-1. The peak at 1240.05 was attributed to C-N stretch of amine. The IR spectra of physical mixture of VNF+HPMC and VNF+sodium alginate also showed respective peaks of drug with small shifts within their concerned range with other respective peaks of HPMC and alginates. This revealed the presence of drug with no interaction which proved its compatibility. There was no appearance of new bands in IR spectra confirming that it did not show change in drug structure. FT-IR spectral analysis confirms that there is no appearance or disappearance of any characteristic peaks of pure drug VNF in the physical mixture of all other extended release excipients (Figure 2). Lactose and magnesium stearate which shows incompatibility in DSC studies were found compatible in FT-IR study as characteristic absorption bands of VNF were well retained in the spectra indicating no significant interactions.

 

Figure 2. Comparative FT-IR study of pure drug VNF (A), physical mixtures (B, C) and whole ER tablet component mixtures (D)

 

Table 2. Formulation composition of VNF extended release tablet

 

Table. 3. Pre-compression properties of directly compressible powder blend

 

Evaluation of pre-compression properties:

Extended release tablet of VNF were successfully prepared by direct compression method using varying quantity of HPMC K4M as hydrophilic swellable release retardant polymer with cationic polymer. All other mixture excipients used in tablet preparation were found compatible with the drug in the above studies (Table 2).

 

The directly compressible powder blend was evaluated for parameters like bulk density, tapped density, compressibility index, and angle of repose, Hausner ratio as shown in Table 3. The bulk density of the powder was in the range of 0.456 to 0.498gm/ml; the tapped density was in the range of 0.440 to 0.460gm/ml, which indicates that the powder was not bulky. The angle of repose of the formulations with lactose in larger quantity was in the range of 15.12º to 18.52º, which indicated good flow of the powder. The Carr’s index was found to be in the range of 3.63 to 9.69 indicating moderate to fairer compressibility of the tablet blend.

 

The Hausner ratio lays in the range 0.911 to 0.964 confirming good flow characteristics for direct compression tablets. The results of Hausner’s ratio were found to be lesser than 1.25 which indicates better flow properties. The results of angle of repose (<30) indicates good flow properties of the powder. This was further supported by lower compressibility index values. Generally compressibility values up to 15% results in good to excellent flow properties.

 

Evaluation results of post compression properties of tablets:

The physical properties of different batches of extended release tablets were given in (Table 4). Tablet mean thickness was almost uniform in all the formulations. The thickness varies between 3.012±0.01 to 3.96±0.03 mm. The prepared tablets in all the formulations possessed good mechanical strength with sufficient hardness in the range of 3.5±0.06 to 4.7±0.06kg/cm². Friability values below 1% were an indication of good mechanical resistance of the tablets. All the tablets from each formulation passed weight variation test, as the % weight variation was within the pharmacopoeial limits of ±5% of the weight. The weight variation in all the six formulations was found to be 202±2.45mg to 198.0±2.20 mg. The percentage drug content of all the tablets was found to be between 96.19±0.32 to 98.69±0.25% which was within the acceptable limits.

 

Drug release characteristics:

For successful extended release of drugs, either soluble or insoluble it is essential that polymer hydration and surface gel layer formation are quick and consistent to prevent tablet disintegration and premature drug release. The dissolution rate profile of all the formulations showed that a higher amount of HPMC K4M in tablet composition resulted in reduced drug release.

 

It indicates, the release was extended with the increase in HPMC percentage in tablets due to the increased per­centage of swelling and the decreased percentage of ero­sion¹⁹.

 

The more the concentration of HPMC, thicker the gel layer offers more resistance to the drug diffu­sion and gel erosion²⁰ which results in the incomplete release. Sodium alginate matrix had the ability to provide a sustained release for highly water-soluble drug even in the pres­ence of water-soluble excipients like HPMC K4M²¹. The com­bined matrix when exposed to an acidic environment, the HPMC hydrates to form a gel layer at the surface of the tablet while the sodium alginate remains insoluble, acting as a barrier to diffusion of the drug²². Sodium alginate precipitates in the hydrated gel layer as alginic acid.

 

Table 4. Post compression properties of prepared tablets

 

This alginic acid then provides a firm structure to the gel and retards rate of erosion. Their proportion had significant effect on the release profiles²³. The drug release profiles of various tablets were shown in Figure 3 and Figure 4.

 

Formulation F-5 having a composition of 20.0% w/w HPMC K4M with 10% sodium alginate provide a good hardness of 4.2Kg/cm² and exhibit predetermine release up to 12 hours than all other formulations (Figure 4). At higher percentage of HPMC in tablets, when in contact with release medium, HPMC may swell and form a thick gel, thus may decrease the size of the pores present in the tablet and further reducing the drug release. Formulation F-5 which showed promising results, were subjected to stability studies at ambient room conditions for 3 months. After 3 months, extended release tablets did not show any change in physical appearance or drug content.

 

Release data revealed that optimized batch F5 follow zero-order drug release followed by Higuchi spherical matrix release as good linearity (R²) was observed with both these models (Table 5). However, the best linearity (R² = 0.998) was obtained in Korse-Mayer peppas models. The release exponent n was 0.81, which indicate a coupling of the diffusion and erosion mechanism so-called non-Fickian or anomalous diffusion and may indicate that the drug release is controlled by more than one process.

 

Figure 3. In-vitro drug release profile of F1, F2 and F3 extended release formulations

Figure 4. In-vitro drug release profile of F4, F5, F6 and F7 extended release formulations

 

Table 5. Release kinetic data for evaluation of drug release mechanism

 

CONCLUSION:

The results showed the utility of thermal analysis as a rapid and convenient method of screening drug candidate and some excipients during pre-formulation studies, because it permits the assessment of excipients compatibility or demonstration of drug-excipient interaction or incompatibility. In this study it was possible to observe the interactions of the VNF with magnesium stearate and lactose. It has been revealed that excipient such as HPMC K4M in combination with ionic polymers can be used to modulate drug release. Formulation F-5 having a composition of 20.0% w/w HPMC K4M and 10% sodium alginate exhibit predetermine drug release up to 12 hours following diffusion controlled swelling and slow erosion. The slower drug release profiles observed with polymer blend formulations may be attributed to the higher gel strength and slower erosion rate in these matrices. In summary, the combination of HPMC with ionic polymers in ER tablet provides robust formulations which are insensitive to hydrodynamic conditions. The optimized formulation was stable after 45 days of accelerated stability study as there were no significant changes in hardness, drug content and extended release pattern.

 

CONFLICT OF INTEREST:

The author confirms no conflicts of interests.

 

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Received on 01.11.2019           Modified on 11.01.2020

Accepted on 06.03.2020         © RJPT All right reserved