INTRODUCTION:

Selection of excipients such as diluents, binders, disintegrants, lubricants, antiadherants, and glidants for an impending formulation is determined earlier from the preformulation study based on the result of the compatibility experiment. Formulation of dosage form, especially in solids such as tablets or capsules requires knowledge of the chemical interaction of the drug substance with adjuvants. Adjuvants or excipients may be numerous in a drug product, as they serve as functioning agents of the manufacturing process. The excipients facilitate the granulate flow and tablet-compressing operation, as well as providing product with good bioavailability and patient acceptability. Excipients present in the tablets are bulking and filling agents, disintegrating agents, lubricating agents, coloring agents, taste masking agents and stabilizers. They may be found in amounts larger than that of the active substance or in smaller quantities.¹

The effect of excipients on pharmaceutical stability appeared in the literature as early as the mid 1950’s. The earliest studies examined only physical appearance. Attempts were made to formalize visual observation by developing appropriate scoring systems; a refinement was tristimulus reflectance measurements.²

As analytical techniques were developed for monitoring stability of the drug substance; they were applied to excipient compatibility testing. When the problem of dosage form stability was recognized, compatibility testing was a first attempt to address it.³Conventional methods of detecting drug-excipient interactions by accelerated stability studies are time consuming and tedious. Differential Scanning Calorimetry (DSC) is fast and reliable method to screen drug excipient compatibility and provide maximum information about the possible interactions⁴. Various techniques like diffuse reflectance spectroscopy⁵, accelerated storage tests, TLC, IR⁶, and X-ray⁷ are employed for detection of possible interactions and incompatibility.

Van Dooren has recommended the use of the DSC in combination with short time stress in order to evaluate DSC curve more easily.⁸In DSC, samples were subjected to a higher temperature range, which may pose a major drawback in identifying the interaction occurring at ambient conditions. Transformation or interactions occurring at this temperature may not take place at room temperature. Hence DSC should not be used as the only tool for studying the drug / excipient interactions. DSC measures the heat loss or gain resulting from physical or chemical changes within sample as function of temperature. Examples of endothermic (heat-absorbing) process are fusion boiling, sublimation, vaporization, desolvation, solid-solid transitions and chemical degradation. Crystallization and degradation are usually exothermic processes⁹.In general, provided that no new thermal events occur, no interaction can be assigned. Chemical interactions are indicated by the appearance of new peaks or where there is grossbroadening or elongation of an exo- or endothermicchange. Second order transitions produce changesin the baseline. Such observations may be indicativeof the production of eutectic or solid-solution type melts. The excipient is then probably chemicallyreactive and incompatible with the drug, and shouldbe avoided. Where an interaction is suspected butthe thermal changes are small, the incompatibilityshould be confirmed by other techniques.⁸

Non thermal methods such as IR spectroscopy and assay is used in the compatibility study of drug and excipients. In IR spectroscopy the realised interactions between drug and excipients discovered and proved with the following important characteristics: appearance of new IR absorption band(s); broadening of band (s); alteration in intensity. The comparison of IR spectra of the drug alone, of the excipient alone and simple physical mixture of the drug and excipients secures the greatest precision of analysis. Also, another nonthermal method for determination of compatibility is to carry out assay of the drug i.e., the percent drug content determined by analyzing the samples of drug excipient mixture (1:1) after exposure to stress conditions as well as room temperature samples. If any degradation of drug occurs due to interaction between drug and excipients it will be evident from the low percent of drug detected in assay.

MATERIALS AND METHODS:

Materials:

Chemicals:

Aceclofenac BP (Aristo Pharmaceuticals Pvt. Ltd.Mumbai), Starch 1500 (Colorcon Asia Pvt.Ltd. Goa), Croscarmellose Sodium, Sodium starch glycolate (Maple Biotech Pvt. Ltd., Pune) Methanol UV grade (Loba Chemicals, Mumbai), KBr.

Instruments:

Differential Scanning Calorimeter (Mettler Toledo, Software –Pyris Manager), UV-Visible Spectrophotometer (Jasco-530), Fourier Transform IR Spectrophotometer (Jasco-460 plus).

Methods:

The compatibility study between Aceclofenac and Starch 1500, Croscarmellose Sodium, Sodium starch glycolate was carried out by Differential scanning calorimetry (DSC) and results of DSC were confirmed by using non thermal methods as FTIR and Assay for the samples kept at stress condition (i.e.55°C for 3 weeks).^8,12

I. Thermal method:

Differential scanning Calorimetry (DSC) : Thermograms of individual excipients, drug and 1:1 mixture of drug excipients were obtained. Samples (1-10 mg) were sealed in flat bottomed aluminium pans and heated over a temperature range of 50- 250°C at a rate of 20°C /min. in a nitrogen atmosphere using Mettler Toledo (Software-Pyris manager).

II. Non thermal method:

A) FTIR : Spectra of individual excipients, drug and 1:1 mixture of drug and excipients were obtained. Samples were prepared by grinding drug, excipients with KBr (1:20) and then, pressing the powder in the sample holder and placed in IR chamber and spectra of individual drug, excipients and their physical mixture were obtained.

b) Assay ¹³ : The percent content of drug was found out from 1:1 mixture of drug and excipients by carrying out chemical assay.

Standard Preparation: Aceclofenac 50 mg was accurately weighed in 100 ml volumetric flask and 30 ml methanol was added and contents dissolved and volume was adjusted to 100ml by methanol and 2 ml from this solution was transferred to 50ml volumetric flask and volume adjusted to 50ml with methanol.

Sample Preparation: From the physical mixture of drug and excipients sample equivalent to 50 mg of Aceclofenac was taken in 100 ml volumetric flask and 30 ml methanol was added and sonicated for 5 min. to dissolve the contents, volume was adjusted to 100 ml by methanol and solution filtered by using Whatman filter paper no 41, 2 ml from this filtrate was transferred to 50 ml volumetric flask and volume adjusted to 50 ml by using methanol. Aceclofenac contents of standard and sample were determined by measuring UV absorbance at 275 nm by using methanol as blank.

RESULT AND DISCUSSION:

I) Thermal Methods:

Differential Scanning Calorimetry:

The thermal characteristics of the samples are summarized in table 1.Figure:1 shows the thermogram of pure Aceclofenac (A), Starch-1500(B) and its mixture(C). The thermogam of pure Aceclofenac(A) showed a single sharp endothermic peak with an onset temperature (To) of 153.387°C, peak temperature (Tp) of 156.368°C and recovery to baseline (Tb) at 159.795°C(Figure :1). The peak temperature represents the melting of Aceclofenac. Besides this an exothermic peak is evident at about 50°C of intensity +1.682.This might indicate a conversion to amorphous form followed by a plateau indicating glass transition. The thermogram of Aceclofenac -Starch 1500 mixture (C) shows a single sharp endothermic peak with an onset temperature (To) of 141.737°C and peak (Tp) at 147.383°C. This decrease as well as the decrease in peak height from 15.546 to 3.6134 is due to the dilution effect of the excipient. The exothermic peak at about 50°C shows a potentiation of intensity to 3.3 indicating an interaction between Aceclofenac and starch 1500. However this cannot be considered as a significant incompatibility between Aceclofenac and Starch 1500.

Figure: 2 shows thermogram of Aceclofenac (A), Croscarmellose Sodium (B) and their mixture(C). Thermogram of mixture shows a broadening of the peak for Aceclofenac is seen with an onset at 130.792°Cand peak at 141.757°C. This simply reflects a parallel shift of the melting endotherm to the left. There is significant decrease in peak height to 0.7725 and complete disappearance of exothermic peak this indicates interaction.

Table:1) Thermal characteristics of Aceclofenac and tablet excipients.

Sr. No.	Drug /Excipient	Onset (To^oC)	Peak (Tp^oC)	Recovery (Tb^oC)	Area (mJ)	Delta H J/g
1	ACF	153.387	156.368	159.795	214.334	107.167
2	Starch 1500	91.147	130.331	281.246	646.866	281.246
3	ACF + Starch 1500	141.737	147.383	151.095	69.440	33.067
4	CMC Sodium	92.103	130.525	163.685	343.304	156.047
5	ACF + CMC Sodium	130.792	141.757	148.609	39.633	16.514
6	SSG	123.307	134.884	148.122	90.063	39.158
7	ACF + SSG	109.391	133.825	152.596	165.653	75.070

Abbreviations: ACF: Aceclofenac, CMC Sodium: Croscarmellose Sodium SSG: Sodium Starch glycollate

DSC thermogram of Aceclofenac with excipients

Fig: 1) DSC Thermogram of Aceclofenac (A), Starch -1500(B), Aceclofenac + Starch -1500 (C)

Fig: 2) DSC Thermogram of Aceclofenac (A), Croscarmellose Sodium (B), Aceclofenac + Croscarmellose Sodium(C)

In thermogram of Aceclofenac and Sodium starch glycolate mixture (Figure: 3) there is complete disappearance of Aceclofenac peak. The peak that is seen has an onset temperature (To) of 109.391°C and a recovery to baseline at 152.596°C. The peak height for mixture is 1.9668. The onset temperature (To) for pure SSG is 123.307°C and recovery to baseline (Tb) is seen at 148.122°C the peak height is 1.5786 indicating a parallel shift of excipient to left.

Fig: 3) DSC Thermogram of Aceclofenac (A), Sodium starch glycollate (B), Aceclofenac + Sodium starch glycollate (C)

II) Nonthermal methods:

A) IR Study: From the IR spectra (Figures: 4 - 9) of the physical mixture of drug and excipients, it was found that there was no shifting and disappearance of the prominent peaks of the Aceclofenac (Table: 2 and 3) in samples kept at room temperature as well under stress condition of 55°C for 3 weeks. This indicates that there is no interaction between Aceclofenac and excipients used in the tablet formulation i.e. there is no incompatibility between Aceclofenac and the tablet excipients.

Table: 2) Interpretation of IR spectrum of Aceclofenac (Stress condition samples: 55°C for 3 weeks)

Sr. No.	IR Signal(cm^-1)	Remark
1	3318	N-H Stretch
2	1717
3	750	Disubstituted Ar- ring
4	1590	N-H deformation
5	717	C-Cl
6	1507	Ar - ring

Figure:4 )Overly IR spectra of Aceclofenac (A),Croscarmellose Sodium(B), Aceclofenac + Croscarmellose Sodium mixture (C) (Ambient Condition Sample)

Figure:5) Overly IR spectra of Aceclofenac (A), Sodium starch glycollate (B), Aceclofenac + Sodium starch glycollate mixture (C) (Ambient Condition Sample)

Figure:6 )Overly IR spectra of Aceclofenac (A), Starch 1500 (B), Aceclofenac + Starch1500 mixture(C) (Ambient Condition Sample)

IR Spectrum of Aceclofenac with excipents (Stress Condition Samples: 55°C for 3 weeks)

Figure:7 )Overly IR spectra of Aceclofenac (A),Croscarmellose Sodium(B), Aceclofenac + Croscarmellose Sodium mixture (C) (Stress Condition Samples: 55°C for 3 weeks)

Figure:8) Overly IR spectra of Aceclofenac (A), Sodium starch glycollate (B), Aceclofenac + Sodium starch glycollate mixture (C) (Stress Condition Samples: 55°C for 3 weeks)

Figure:9) Overly IR spectra of Aceclofenac (A), Starch 1500 (B), Aceclofenac + Starch1500 mixture(C) (Stress Condition Samples: 55°C for 3 weeks).

C) Assay:

The percent drug content of Aceclofenac was found between 99-101% (Table: 3) in all physical mixtures (1:1) of drug and excipients which complies with BP limits (99-101%) mentioned in monograph of Aceclofenac, which shows that there was no degradation or interactions occurring between Aceclofenac and tablet excipients for the samples kept at room temperature and stress condition (i.e.55°C for 3 weeks).

CONCLUSION:

Compatibility studies performed by Differential Scanning Calorimetry (thermal method) and FTIR, assay (nonthermal method) showed compatibility of Aceclofenac with Starch 1500 and Croscarmelose sodium except sodium starch glycollate. However sodium starch glycollate was found to be compatible with Aceclofenac in FTIR and assay. From this we can conclude that where an interaction is suspected, the incompatibility should be confirmed by other techniques.

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Sr. No	Sample	Percent Drug Content (Ambient condition samples)	Percent Drug Content (Stress condition samples: 55°C for 3 weeks)
1	ACF + CMC Sodium	99.26	99.24
2	ACF + SSG	99.84	99.84
3	ACF + Starch 1500	99.97	99.53