STABLE FORMULATION OF ACECLOFENAC AND THIOCOLCHICOSIDE TABLETS
HTML Full TextSTABLE FORMULATION OF ACECLOFENAC AND THIOCOLCHICOSIDE TABLETS
V Sai Shivram, Swapnil Deshmukh*, Vishal Dalavi and Dipak Sonawane
Research and Development Department, Tulip Lab Pvt Ltd., Ranjangaon, Pune, Maharashtra, India
ABSTRACT: The present study relates to the stable fixed dose combination comprising of Aceclofenac as a glycolic acid ester of Diclofenac is having analgesic and anti-inflammatory action and Thiocolchicoside, as a glycosulfurated analogue of colchicine which is well known centrally acting muscle relaxant in unit dosage form and to the preparation method thereof. Aceclofenac is very susceptible to decomposition under hydrolytic, oxidative stress and exposure to light. The major degradation product identified was diclofenac, which was detected as an impurity in the formulation. Many of the marketed formulation of Aceclofenac tablets having problem of high content of diclofenac impurity. Diclofenac having more gastrointestinal adverse effects such as gastritis, gastrointestinal haemorrhage, haemorrhagic diarrhoea, gastrointestinal ulcer than that of Aceclofenac. It was challenge to develop Aceclofenac tablet formulation having diclofenac impurity within compendial limit. The compatibilty of Aceclofenac with various tableting excipients was investigated physically and by means of Differential Scanning Calorimetry (DSC). Aceclofenac alone and with other excipients in 1:1 binary mixtures were investigated before and after accelerated storage. An interaction was observed between Aceclofenac and magnesium stearate. It was also observed that conversion of Aceclofenac to diclofenac was decreased when used in combination of Thiocolchicoside by using specific method of manufacture. Hydroxypropyl cellulose as a binder also play important role to prevent the conversion of Aceclofenac to diclofenac
Key words: |
Aceclofenac, Thiocolchicoside, Diclofenac, Magnesium stearate, Incompatibility, Tablet
INTRODUCTION: Non Steroidal Anti-Inflammatory Drugs (NSAIDs) are among the most frequently prescribed categories of drugs worldwide in the treatment of pain and inflammation in many conditions. Traditionally NSAIDs account for 70% of the total prescription for pain. NSAIDs help in relieving pain in patients by blocking cyclooxygenase (COX) enzymes that lead to secretion of prostaglandins, which causes pain and inflammation 1, 2.
Though NSAIDs are widely used for long-term care, it is now well established that they are associated with development of upper gastrointestinal damage, including mucosal erosions, ulcers and life threatening conditions like perforation and hemorrhage. This life threatening consequences led to the development of cyclo-oxygenase-2 inhibitors. The potential advantage of Cyclooxygenase-2 (COX-2) inhibitors is that they have fewer adverse effects on the gastrointestinal tract as a result of having less inhibitory effect on the gastro-protective prostanoids produced by COX-1 enzyme in the Gastrointestinal tract (GIT). This advantage of COX-2 selective NSAIDs has been demonstrated in many trials 3-5.
Aceclofenac is an effective analgesic and anti-inflammatory agent; through these properties it provides greater symptomatic relief in a variety of painful conditions 6. It has also shown to exert effects on a variety of mediators of inflammation. The drug inhibits synthesis of inflammatory cytokines like interleukin (IL)-1β and tumor necrosis factor (TNF) and inhibits prostaglandin E2 (PGE2) production 7. Aceclofenac selectively block COX-2 enzyme and thus reduces the risk of peptic ulceration. Aceclofenac is white to almost white, crystalline powder practically insoluble in water, freely soluble in acetone, soluble in ethanol (96 percent). Chemically it is [[[2-[(2,6-chlorophenyl) amino] phenyl]acetyl]oxy] acetic acid.
Although Aceclofenac is having less gastrointestinal adverse effect, but it is very susceptible to decomposition under hydrolytic stress (acidic and alkaline) and oxidative stress to its analog diclofenac, a major degradation product. Degradation reaction is given below in Fig 1.
FIG. 1 DEGRADATION REACTION FOR ACECLOFENAC
Diclofenac a analog of Aceclofenac is an already established Non-Steroidal Anti-Inflammatory drug with analgesic and antipyretic properties. Diclofenac exerts its action via inhibition of prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency. COX-1 play important role in housekeeping such as it protects gastric mucosa, regulate gastric acid and maintain normal functions of the kidney by stimulating prostaglandins. COX-2 is involved in the synthesis of prostaglandins that causes pain and inflammation in the body 1, 8. Due to non selectivity Diclofenac has shown increased incidence of adverse effects like abdominal pain, dyspepsia, diarrhoea, heartburn and GI ulcer. Detail Pharmacological action of COX-1 and COX-2 enzymes are diagrammatically demonstrated below in Fig. 2.
FIG. 2: PHARMACOLOGICAL ACTION OF COX-1 AND COX-2 ENZYMES
Due to high degradation susceptibility of Aceclofenac, many of the marketed formulation of Aceclofenac tablets are having problem of high content of diclofenac impurity. Official compendium have fix limit of diclofenac in Aceclofenac Tablets to 5.0 %, but in investigation many of the marketed formulation shows content of diclofenac on higher side i.e. more than 5.0 %.
Compatibility of an active pharmaceutical ingredient (API) with excipients is one of the key factor influencing the stability of a formulation, because excipients can interact with API both chemically and physically. Chemical interactions between API and excipients result in a reduction of the quantity of the API, which can influence the absorption and therapeutic effect. Physical interactions can alter the physicochemical parameters of the components, e.g. the solubility, the dissolution rate and finally the bioavailability. Adsorption of drug molecules onto the surface of excipients can render the drug unavailable for dissolution and diffusion, which can result in reduced bioavailability. For example, antibacterial activity of cetylpyridinium chloride was decreased when magnesium stearate was used as lubricant in tablet containing cetylpyridinium chloride; this was due to adsorption of cetylpyridinium cation by stearate anion on magnesium stearate particle 9.
In one of the investigation, it was observed that dissolution of drug was decreased due to adsorption of drug on the surface of microcrystalline cellulose. In a similar context, adsorption of novel k-opoid agonist by microcrystalline cellulose led to incomplete drug release from the capsules. Adsorption may also initiate chemical breakdown. Colloidal silica was shown to catalyze nitrozepam degradation in tablet dosage form, possibly by adsorptive interactions altering electron density in the vicinity of the labile azo group and thus facilitating attack by hydrolyzing entities10. Investigation of the incompatibility between the components of the dosage form is critical in the early stages of the development of a stable dosage form. Differential scanning calorimetry (DSC) has been widely used to assess incompatibility between formulation components, because the method is fast and versatile and requires very small quantity of sample 11.
Most commonly used muscle relaxants are central nervous system depressants. Although these groups of drugs usually help to reduce spasticity, but decrease in muscle tone elsewhere, may lead to a decrease in the mobility of the patient. Also the development of sedation, is found to be a major limiting factor in the use of muscle relaxants for the treatment of Acute Low Back Pain (LBP), as they can affect daily activities and decrease working capabilities 12, 13. Hence, these limiting factors in the use of muscle relaxants raised a need for an ideal muscle relaxant devoid of effects on psychomotor performance, free of sedation and higher tolerability.
Thiocolchicoside is a semi-synthetic derivative of colchicine, a natural glycoside of Superba gloriosa. It’s in- vitro profile shows affinity for the inhibitory glycine and GABA A receptors and therefore the compound is endowed with glycinomimetic activity and is being used in rheumatology and orthopaedic field for its myorelaxant property 14, 15. It has been reported that thiocolchicoside produces muscle relaxation without any sedative side effects. It is indicated for the adjunctive treatment of muscle spasm in acute low back pain (LBP) 16.
Thiocolchicoside is yellow crystalline powder. It is soluble in water, slightly soluble in ethanol and insoluble in chloroform. It is a glycosulfurated analogue of colchicine and is a well known centrally acting muscle relaxant used in the treatment of musculoskelatel disorders. Chemically it is N-[(7S)-3-(β-D-Glucopyranosyloxy)-1,2-dimethoxy-10-(methylsulfanyl) – 9 – oxo - 5, 6,7,9 tetrahydrobenzo[a]heptalen-7-yl] acetamide.
The primary objective of the study was to develop stable Aceclofenac, Aceclofenac and Thiocolchicoside tablets formulation with minimum diclofenac impurity so that it will comply with all the regulatory requirements.
Many of the marketed formulation of Aceclofenac tablets use common tableting excipients such as microcrystalline cellulose, croscarmellose sodium, povidone, maize starch and magnesium stearate, but in literature survey it was reported that these formulations have problem of high content of diclofenac impurity in stability or during shelf life. Incompatibility of Aceclofenac and magnesium stearate is also reported in the literature. So to find out route cause and for the selection of the appropriate excipients in the formulation it was decided to carry out the drug-excipients compatibility study. Commonly used excipients such as microcrystalline cellulose as a diluent, croscarmellose sodium, crospovidone and sodium starch glycolate as a disintegrants, maize starch, povidone, hydroxypropyl cellulose as a binder and magnesium stearate, stearic acid, glyceryl palmitostearate and sodium stearyl fumarate as a lubricant were subjected to the compatibility study.
MATERIAL AND METHOD:
Material:
Aceclofenac was obtained from Amoli organics Pvt. Ltd. Vapi, Gujarat, India. Thiocolchicoside was obtained from Alchem International Ltd. Mumbai, India. Microcrystalline Cellulose (NB entrepreneurs), Crospovidone (Ashland, U.S.A.), Croscarmellose Sodium (FMC Biopolymer, U.S.A.), Sodium starch glycolate (Amishi drugs and chemicals Pvt. Ltd., Ahmedabad, Gujarat, India), Hydroxypropyl Cellulose (Ashland, U.S.A.), Maize starch (Universal starch chem allied Ltd., Mumbai), Povidone K-30 (ISP, India), Colloidal silicon dioxide (Evonic Ind., Germany), Glyceryl palmitostearate (Gattefosse, France), Stearic Acid (Cognis, Germany), Sodium stearyl fumarate (JRS Pharma., Germany), Opadry White YS-1R-7003 (Colorcon, India), Opadry Yellow 13B520019 (Colorcon, India).
Pre-formulation Study:
Drug-excipient compatibility study was performed using Aceclofenac with the excipients to be used in the formulations. Aceclofenac alone and with other excipients in 1:1 binary mixtures were physically investigated before and after accelarated storage. It was also confirmed by the differential scanning calorimetry (DSC).
Hydroxypropyl cellulose was chosen as a binder, as it is a nonionic water-soluble cellulose ether with a remarkable combination of properties. It combines organic solvent solubility, thermoplasticity and surface activity with the aqueous thickening and stabilizing properties.
Crospovidone and Croscarmellose sodium were selected as a disintegrants for the development of tablet formulation as they have less pH dependent disintegration profile.
For selection of suitable lubricant out of the choice available, magnesium stearate, glyceryl palmitostearate, sodium stearyl fumarate and stearic acid were investigated for compatibility study with Aceclofenac at normal room temperature and acceletated stability condition with and without moisture and from the DSC analysis it was concluded that along with magnesium stearate, sodium stearyl fumarate was also incompatible with Aceclofenac. Hence it was decided to use glyceryl palmitostearate and stearic acid as lubricant. Proposed list of excipients for development of Aceclofenac, Aceclofenac and Thiocolchicoside tablets formulation were given below in Table 1.
TABLE 1: PROPOSED LIST OF INGREDIENTS TO BE USED FOR DEVELOPMENT
Sr. No. | Name Ingredients | Uses |
1 | Aceclofenac | Active pharmaceutical ingredient |
2 | Thiocolchicoside | Active pharmaceutical ingredient |
3 | Microcrystalline Cellulose | Diluent |
4 | Crospovidone | Disintegrant |
5 | Hydroxypropyl Cellulose | Binder |
6 | Croscarmellose Sodium | Disintegrant |
7 | Glyceryl palmitostearate | Lubricant |
8 | Stearic Acid | Lubricant |
9 | Opadry White (YS-1R-7003) | Coating agent |
10 | Opadry Yellow (13B520019) | Coating agent |
Drug profiles are given in Table 2
TABLE 2: DRUG PROFILE
In this study following three different formulation trials were conducted based on the observations from DSC studies.Method of Manufacture:
- Aceclofenac Tablet 100 mg
- Aceclofenac 100 mg and Thiocolchicoside 4 mg Tablet
- Aceclofenac 100 mg and Thiocolchicoside 8 mg Tablet
Detail composition is given in Table 3.
TABLE 3: DETAIL COMPOSITION OF FORMULATIONS
Sr. No. | Name of ingredients | Aceclofenac Tablets 100 mg | Aceclofenac 100 mg and Thiocolchicoside 4 mg Tablets | Aceclofenac 100 mg and Thiocolchicoside 8 mg Tablets |
Dry mixing | ||||
1 | Aceclofenac | 100.0 | 100.0 | 100.0 |
2 | Microcrystalline Cellulose PH101 | 40.0 | 40.0 | 40.0 |
3 | Crospovidone
(Polyplasdone XL-10) |
7.0 | 7.0 | 7.0 |
Granulation | ||||
4 | Thiocolchicoside | -- | 4.0 | 8.0 |
5 | Hydroxypropyl Cellulose
(Klucel LF) |
2.0 | 2.0 | 2.0 |
6 | Purified Water* | q.s. | q.s. | q.s. |
Lubrication |
||||
7 | Microcrystalline Cellulose PH102 | 73.6 | 24.3 | 64.4 |
8 | Croscarmellose Sodium
(Ac-Di-Sol) |
15.0 | -- | 15.0 |
9 | Glyceryl palmitostearate
(Precirol ATO-5) |
2.4 | 1.8 | 2.4 |
10 | Stearic Acid | -- | 0.9 | 1.2 |
Weight of uncoated tablet |
240.0 | 180.0 | 240.0 |
Sr. No. | Name of ingredients | Aceclofenac Tablets 100 mg | Aceclofenac 100 mg and Thiocolchicoside 4 mg Tablets | Aceclofenac 100 mg and Thiocolchicoside 8 mg Tablets |
Film Coating | ||||
11 | Coating Readymix
Opadry White (YS-1R-7003) |
4.0 | -- | -- |
12 | Coating Readymix
Opadry Yellow (13B520019) |
-- | 4.5 | 6.0 |
13 | Isopropyl Alcohol* | q.s. | q.s. | q.s. |
14 | Dichloromethane* | q.s. | q.s. | q.s. |
Weight of coated tablet | 244.0 | 184.5 | 246.0 |
* Does not form the part of final product.
Wet granulation approach was used for the manufacturing of tablet formulation. In first trial aceclofenac, microcrystalline cellulose and crospovidone were dry mixed and granulated with hydroxypropyl cellulose binder solution. Granules were dried and sifted through appropriate sieve and finally blended with microcrystalline cellulose, croscarmellose sodium and glyceryl palmitostearate. In combination products Aceclofenac 100mg and thiocolchicoside 4mg tablets and Aceclofenac 100mg and thiocolchicoside 8mg tablets, thiocolchicoside is dissolved along with hydroxypropyl cellulose in purified water and added as binder solution. Aceclofenac along with microcrystalline cellulose and crospovidone were granulated using thiocolchicoside-hydroxypropyl cellulose binder solution. Granules were dried and sifted through appropriate sieve and finally blended with microcrystalline cellulose, croscarmellose sodium, glyceryl palmitostearate and stearic acid. Lubricated blend from all the three batches were compressed into the tablet dosage form and film coated using the coating ready mix material. Finished tablet formulation was then packed in aluminium strip pack and accelerated stability study of each batch along with the reference product of same strength were conducted for six months.
Evaluation of formulation:
- Weight variation:
Twenty tablets were selected at random and weighed individually. The individual weights were compared with the average weight for determination of weight variation. (IP, BP and USP Limit ± 7.5% of average weight).
- Hardness:
Ten tablets were randomly selected from each batch and hardness of tablets was determined by using Monsanto hardness tester.
- Friability:
Friability indicates the ability of a tablet to withstand mechanical shocks while handling. Friability of the tablets were determined using Electrolab Friabilator and is expressed in percentage (%). Tablets weighed equivalent to 6.5 gm were initially weighed (W1) and placed into the friabilator. The friabilator was operated at 25 rpm for 4 minutes and then the tablets were weighed again. The loss in tablet weight due to abrasion or fracture (W2) was the measure of tablet friability. Percent friability (F) was calculated by using the following formula.
- Disintegration Time:
The disintegration time for all batches were carried out in water (37 ± 2°C) according to USP using tablet disintegration test apparatus. Six tablets were placed individually in each tube of disintegration test apparatus and noted the time taken for the entire tablet to disintegrate completely (IP, BP and USP limit NMT 30 mins for coated tablets).
- Related Substances:
Determination of related substances is important tool to judge the safety, efficacy and stability of product. In this study content of diclofenac in three tablet formulation along with their respective marketed formulations were determined initially and after 6M accelerated stability study by using High performance liquid chromatography (HPLC).
RESULTS AND DISCUSSION:
Pre-formulation results:
Results of preformulation study are given in Table 4 and 5.
TABLE 4: COMPATIBILITY STUDY OF ACECLOFENAC WITH EXCIPIENTS
Compatibility study of Aceclofenac with excipients | ||||||||||
Sr. No. | Composition details | Initial | Room temperature | 40°C/75%RH | ||||||
5 days | 10 days | 15 days | 30 days | 5 days | 10 days | 15 days | 30 days | |||
1 | Aceclofenac | White powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
2 | Aceclofenac + Microcrystalline Cellulose | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
3 | Aceclofenac +Hydroxypropyl Cellulose | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
4 | Aceclofenac + Maize starch | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
5 | Aceclofenac + Povidone | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
6 | Aceclofenac + Croscarmellose sodium | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
7 | Aceclofenac+Sodium starch glycolate | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
8 | Aceclofenac + Crospovidone | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
9 | Aceclofenac + Colloidal anhydrous silica | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
10 | Aceclofenac+ Magnesium stearate | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
11 | Aceclofenac+ Sodium stearyl fumarate | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
12 | Aceclofenac+ Stearic acid | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
13 | Aceclofenac + Glyceryl palmitostearate | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
14 | Aceclofenac + Opadry White (YS-1R-7003) | White to off white powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
15 | Aceclofenac + Opadry Yellow (13B520019) | Pale Yellow powder | NCC | NCC | NCC | NCC | NCC | NCC | NCC | NCC |
NCC– No Characteristic Change
TABLE 5: THERMOANALYTICAL DATA OF ACECLOFENAC AND ACECLOFENAC WITH DIFFERENT LUBRICANTS IN PHYSICAL MIXTURE (1:1 RATIO)
Sr.
No. |
Sample | Condition | DSC DATA | ||
Tonset | Tpeak | Enthalpy | |||
1 | Aceclofenac | Room Temperature | 151.65°C | 153.4°C | 139.5J/g |
2 | Aceclofenac | 12 days, 40°C/75%RH | 151.82°C | 153.41°C | 140.2J/g |
3 | Aceclofenac with 0.5% Moisture | 12 days, 40°C/75%RH | 151.55°C | 153.33°C | 137.4J/g |
4 | Aceclofenac + Mg Stearate | Room Temperature | 75.64°C
177.73°C |
88.73°C
189.98°C |
79.38J/g
4.799J/g |
5 | Aceclofenac + Mg Stearate | 12 days, 40°C/75%RH | 76.48°C
179.57°C |
88.9°C
188.15°C |
79.08J/g
3.313J/g |
6 | Aceclofenac + Mg Stearate with 0.5% Moisture | 12 days, 40°C/75%RH | 94.76°C
117.3°C 174.48°C |
98.38°C
129.45°C 183.97°C |
94.25J/g
17.91J/g 5.475J/g |
7 | Aceclofenac + Glyceryl Palmitostearate (1:1) | Room Temperature | 51.72°C
128.53°C |
57.99°C
144.54°C |
81.37J/g
45.43J/g |
8 | Aceclofenac + Glyceryl Palmitostearate | 12 days, 40°C/75%RH | 49.82°C
58.02°C 131.55°C |
53.27°C
62.43°C 147.01°C |
19.96J/g
16.6J/g 39.27J/g |
9 | Aceclofenac + Glyceryl Palmitostearate with 0.5% moisture | 12 days, 40°C/75%RH | 51.19°C
58.85°C 136.6°C |
54.68°C
62.17°C 147.69°C |
24.03J/g
16.6J/g 45.53 J/g |
10 | Sodium stearyl fumarate | Room Temperature | 57.17°C
95.33°C 127.29°C 195.76°C |
57.64°C
112.85°C 134.02°C 197.03°C |
5.551J/g
77.58 J/g 52.00J/g 28.52J/g |
11 | Aceclofenac + Sodium stearyl Fumarate | Room Temperature | 56.65°C
94.96°C 229.16°C 268.79°C |
57.48°C
104.08°C 248.41°C 274.30°C |
2.978J/g
117.6 J/g 44.85J/g 17.97J/g |
12 | Aceclofenac + Sodium stearyl Fumarate (1:1) | 12 days, 40°C/75%RH | 56.33°C
94.26°C 234.86°C 269.52°C |
58.33°C
104.56°C 248.37°C 276.63°C |
6.292J/g
102.1 J/g 34.58J/g 14.76J/g |
13 | Aceclofenac + Sodium stearyl Fumarate with 0.5% Moisture | 12 days, 40°C/75%RH | 56.54°C
93.7°C 230.09°C 270.19°C |
57.65°C
105.94°C 250.38°C 276.94°C |
3.117J
93.03 J/g 63.83J 17.35J |
14 | Stearic acid | Room Temperature | 51.2°C | 67.8°C | 16.6J/g |
15 | Aceclofenac + Stearic acid | Room Temperature | 49.0°C
151.55°C |
69.8°C
160.5°C |
17.6J/g
141.2J/g |
16 | Aceclofenac + Stearic acid | 12 days, 40°C/75%RH | 45.0°C
145.12°C |
65.8°C
155.5°C |
14.8J/g
137.2J/g |
17 | Aceclofenac + Stearic acid with 0.5% Moisture | 12 days, 40°C/75%RH | 44.9°C
99.3°C 144.55°C |
62.8°C
110.2°C 156.8°C |
16.2J/g
19.8J/g 139.2J/g |
DSC data interpretation:
Aceclofenac:
- The DSC curve of Aceclofenac showed endothermic event between 151.65°C and 153.4°C (ΔHfusion = -139.51J).
- The DSC curve of Aceclofenac stored at 40°C/75% RH for 12 days showed endothermic event between 151.82°C and 153.41°C (ΔHfusion = -140.21J). This demonstrates that there are no remarkable alteration in thermo-analytical profile of drug when stored under stress condition.
- The DSC curve of Aceclofenac with 0.5% moisture stored at 40°C/75% RH for 12 days showed endothermic event between 151.55°C and 153.33°C (ΔHfusion = -137.4J). This demonstrates that there are no remarkable alteration in thermo-analytical profile of drug when stored under stress condition with 0.5% moisture.
Aceclofenac + Magnesium Stearate (1:1)
- The DSC curve of Aceclofenac + Magnesium Stearate (1:1) stored at room temperature showed two endothermic event
- Between 75.64°C and 88.73°C (ΔHfusion = -79.38J)
- Between 177.73°C and 189.98°C (ΔHfusion = -4.799J)
This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Magnesium Stearate.
- The DSC curve of Aceclofenac + Magnesium Stearate (1:1) stored at 40°C/75% RH for 12 days showed two endothermic event
- Between 76.48°C and 88.9°C (ΔHfusion = -79.08J)
- Between 179.57°C and 188.15°C (ΔHfusion = -3.313J)
This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Magnesium Stearate.
- The DSC curve of Aceclofenac + Magnesium Stearate (1:1) with 0.5% moisture stored at 40°C/75% RH for 12 days showed three endothermic event as given below:
- Between 94.76°C and 98.38°C (ΔHfusion = -94.25J)
- Between 117.3°C and 129.45°C (ΔHfusion = -17.91J)
- Between 174.48°C and 183.97°C (ΔHfusion = -5.475J)
This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Magnesium Stearate. The reaction is accelerated in presence of moisture.
Aceclofenac + Glyceryl Palmitostearate (1:1)
- The DSC curve of Aceclofenac + Glyceryl Palmitostearate (1:1) stored at Room Temperature showed two endothermic event
- Between 51.72°C and 57.99°C (ΔHfusion = -81.37J) (due to Glyceryl Palmitostearate)
- Between 128.53°C and 144.54°C (ΔHfusion = -45.43J). (due to Aceclofenac)
This demonstrates that there are no remarkable alteration in thermo-analytical profile of Aceclofenac when stored with Glyceryl Palmitostearate
- The DSC curve of Aceclofenac + Glyceryl Palmitostearate (1:1) stored at 40°C/75% RH for 12 days showed three endothermic event (split in the peak due to Glyceryl Palmitostearate)
- Between 49.82°C and 53.27°C (ΔHfusion = -19.96J)
- Between 58.02°C and 62.43°C (ΔHfusion = -16.6J)
- Between 131.55°C and 147.01°C (ΔHfusion = -39.27J) (due to Aceclofenac)
This demonstrates that though the stress condition has affected the thermo-analytical profile of Glyceryl Palmitostearate, there are no remarkable alteration in thermo- analytical profile of Aceclofenac when stored with Glyceryl Palmitostearate
- The DSC curve of Aceclofenac + Glyceryl Palmitostearate (1:1) with 0.5% moisture stored at 40°C/75% RH for 12 days showed three endothermic event (split in the peak due to Glyceryl Palmitostearate)
- Between 51.19°C and 54.68°C (ΔHfusion = -24.03J)
- Between 58.85°C and 62.17°C (ΔHfusion = -16.6J)
- Between 136.6°C and 147.69°C (ΔHfusion = -45.53J) (due to Aceclofenac)
This demonstrates that though the presence of moisture and the stress condition has affected the thermo-analytical profile of Glyceryl Palmitostarate, there are no remarkable alteration in thermo-analytical profile of Aceclofenac when stored with Glyceryl Palmitostearate.
Aceclofenac + Sodium Stearyl Fumarate (1:1)
- The DSC curve of Aceclofenac + Sodium Stearyl Fumarate (1:1) stored at Room Temperature showed four endothermic event.
- Between 56.65°C and 57.48°C (ΔHfusion = -2.978J)
- Between 94.96°C and 104.08°C (ΔHfusion = -117.6J)
- Between 229.16°C and 248.41°C (ΔHfusion = -44.85J)
- Between 268.79°C and 274.30°C (ΔHfusion = -17.97J)
This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Sodium Stearyl Fumarate.
- The DSC curve of Aceclofenac + Sodium Stearyl Fumarate (1:1) stored at 40°C/75% RH for 12 days showed four endothermic event
- Between 56.33°C and 58.33°C (ΔHfusion = -6.292J)
- 94.26ºC and 104.96ºC (∆Hfusion = - 102.1J)
- Between 234.86°C and 248.37°C (ΔHfusion = -34.58J)
- Between 269.52°C and 276.63°C (ΔHfusion = -14.76J)
The thermo-analytical profile is similar to that of sample stored at room temperature.
This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Sodium Stearyl Fumarate.
- The DSC curve of Aceclofenac + Sodium Stearyl Fumarate (1:1) with 0.5% moisture stored at 40°C/75% RH for 12 days showed four endothermic event.
- Between 56.54°C and 57.65°C (ΔHfusion = -3.117J)
- 7ºC and 105.94ºC (∆H fusion = - 93.03J)
- Between 230.09°C and 250.38°C (ΔHfusion = -63.83J)
- Between 270.19°C and 276.94°C (ΔHfusion = -17.35J)
The thermo-analytical profile is similar to that of sample stored at room temperature as well as under stress condition. This demonstrates that there is a shift in peak due to interaction between Aceclofenac and Sodium Stearyl Fumarate.
Aceclofenac + Stearic acid (1:1):
The DSC curve of Aceclofenac + Stearic acid (1:1) stored at Room Temperature showed two endothermic event.
- Between 49.0°C and 69.8°C (ΔHfusion = -17.6J) (due to Stearic acid)
- Between 151.55°C and 160.5°C (ΔHfusion = -141.2J). (due to Aceclofenac)
This demonstrates that there are no remarkable alteration in thermo-analytical profile of Aceclofenac when stored with Stearic acid.
- The DSC curve of Aceclofenac + Stearic acid (1:1) stored at 40°C/75% RH for 12 days showed two endothermic event
- Between 45°C and 65.8°C (ΔHfusion = -14.8J) (due to Stearic acid)
- Between 145.12°C and 155.5°C (ΔHfusion = -137.2J) (due to Aceclofenac)
This demonstrates that there are no remarkable alteration in thermo-analytical profile of Aceclofenac when stored with Stearic acid in accelerated stress condition.
- The DSC curve of Aceclofenac + Stearic acid (1:1) with 0.5% moisture stored at 40°C/75% RH for 12 days showed three endothermic event
- Between 44.9°C and 62.8°C (ΔHfusion = -16.2J) (due to Stearic acid)
- Between 99.3°C and 110.2°C (ΔHfusion = -19.8J)
- Between 144.5°C and 156.8°C (ΔHfusion = -139.2J) (due to Aceclofenac)
This demonstrates that though the presence of moisture and the stress condition has affected the thermo-analytical profile of Stearic acid, there are no remarkable alteration in thermo-analytical profile of Aceclofenac when stored with Stearic acid.
Formulation results:
Physical parameters of the tablet formulations are given in Table 6.
TABLE 6: PHYSICAL PARAMETERS OF TABLET
Sr. No. | Name of Product | Average weight (mg) | Diameter (mm) | Length (mm) | Width (mm) | Disintegration time (mins) | |
1 | Aceclofenac Tablets 100 mg | Reference product | 190.0 | 8.16 | -- | -- | 45.0 sec. |
Trial Batch
(Tulip) |
247.0 | -- | 11.59 | 5.58 | 25.0 sec. | ||
2 | Aceclofenac 100 mg and Thiocolchicoside 4 mg Tablets | Reference product | 225.0 | 9.0 | -- | -- | 6.0 mins, 12 sec. |
Trial Batch
(Tulip) |
185.8 | 8.18 | -- | -- | 1.0 mins, | ||
3 | Aceclofenac 100 mg and Thiocolchicoside 8 mg Tablets | Reference product | 227.0 | 9.0 | -- | -- | 6.0 mins |
Trial Batch
(Tulip) |
245.9 | -- | 11.62 | 5.62 | 2.0 mins, 21 sec. |
Related Substances:
Contents of Diclofenac Impurity in trial batches and their respective reference product were given in Table 7 and graphically represented in Fig. 3.
TABLE 7: CONTENT OF DICLOFENAC IMPURITY (%)
Sr. no. | Condition | Aceclofenac Tablets 100 mg | Aceclofenac 100 mg and Thiocolchicoside 4 mg Tablets | Aceclofenac 100 mg and Thiocolchicoside 8 mg Tablets | |||
Trial Batch
(Tulip) |
Reference product | Trial Batch
(Tulip) |
Reference product | Trial Batch (Tulip) | Reference product | ||
1 | Initial | 0.097 | 1.64 | 0.14 | 0.42 | 0.04 | 0.15 |
2 | 6M accelerated stability | 0.43 | 5.71 | 0.45 | 2.8 | 0.22 | 0.52 |
FIG. 3: CONTENT OF DICLOFENAC IMPURITY (%)
CONCLUSION: From the above thermoanalytical data it was concluded that Aceclofenac is incompatible with magnesium stearate and sodium stearyl fumarate. Aceclofenac is very susceptible to degradation to its analog diclofenac which is having many gastrointestinal side effects. Degradation of aceclofenac can be reduced by using specific method of manufacturing. Thiocolchicoside along with hydroxypropyl cellulose help in controlling the degradation of Aceclofenac and it acts as a barrier that inhibits degradation of Aceclofenac to its analog diclofenac. It was also proved that concentration of the thiocolchicoside have effect on the degradation of Aceclofenac, as concentration of the thiocolchicoside increases degradation of aceclofenac to diclofenac decreases.
REFERENCES:
- Raut A, Reddy G, Patil S and Dalvi N. Comparative efficacy of combined use of diclofenac with thiocolchicoside and diclofenac alone in orthopedic patients. International Research Journal of Pharmacy 2013; 4(2):164-166.
- Malhotra S, Shafiq N and Pandhi P. COX-2 inhibitors: A CLASS act or just Vigorously promoted. Med Gen Med. Accessed 2004; 4(1):6.
- Goldstein JL, Correa P, Zhao WW, Burr AM, Hubbard RC, Verburg KM, et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclo-oxygenase-2 inhibitors, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001; 96(4):1019-27.
- Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, et al. A randomized trial comparing the effect of rofecoxib, a novel cyclo-oxygenase-2 inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Refocoxib osteoarthritis Endoscopy Study group. Gastroenterology 1999; 117(4):776-83.
- Hawakey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E, et al. Comparision of the effect of rofecoxib, ibuprofen, and a placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double blind, placebo controlled trial. The Rofecoxib osteoarthritis Endoscopy Multinational study group. Arthritis rheum 2000; 43:370-7.
- Dooley M, Spencer CM and Dunn CJ. Aceclofenac: a reappraisal of its use in the management of pain and rheumatic disease. Drugs. 2001; 61:1351-78.
- Hinz B and Brune K. Pain and osteoarthritis: new drugs and mechanisms. Curr opin rheumatol 2004; 16:628-33.
- Patil P, Jaida J, Palani A, Anandam B and Rao K. A comparative study of efficacy and safety of diclofenac and aceclofenac in the treatment of osteoarthritis patients. Journal of Drug Delivery and Therapeutics 2012; 2(4):139-143.
- Mackay KM, Michael R, Richards E and Xing JZ. Excipients interaction with Cetylpyridinium chloride activity in tablet based lozenges. Pharm. Res. 1996; 13:1258-1264.
- Czaja J and Mielck JB. Solid-State Degradation Kinetics of Nitrazepam in the Presence of Colloidal Silica. Pharm. Acta. Helv. 1982; 57(5–6):153–155.
- Aigner Z, Heinrich R, Sipos E, Farkas G, Ciurba A, Berkesi O, et al. Compatibility studies of aceclofenac with retard tablet excipients by means of thermal and FT-IR spectroscopic methods. J Therm Anal Calorim 2011; 104:265–271.
- Ketenzi A, Ozcan E and Karamursel. S. Assessment of efficacy and psychomotor performances of thiocolchicoside and tizanidine in patients with acute low back pain. International Journal of Clinical Practice 2005; 59:764-770.
- Woolfrey S and Kapur D. Pain, Neurological and Psychological Disorders. In: Walker R, Whittlesed C. Clinical Pharmacy and Therapeutics. Churchill Livingstone. Elsevier. London 2007; 4: 480.
- Patat A, Klein MJ, Surjus A, Renault M, Rezvani Y and Granier J. Effects of acute and repeated doses of two muscle relaxants chlormezanone and thiocolchicoside, on vigilance and psychomotor performance of healthy volunteers. Human Psychopharmacology 1991; 6:285–292.
- Gabriele f and Indena s.p.a. Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity. WO/2007/009772, 2007 January 25.
- https://en.wikipedia.org/wiki/Thiocolchicoside.
How to cite this article:
Shivram VS, Deshmukh S, Dalavi V and Sonawane D: Stable Formulation of Aceclofenac and Thiocolchicoside Tablets. Int J Pharm Sci Res 2016; 7(4): 1513-23.doi: 10.13040/IJPSR.0975-8232.7(4).1513-23.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Article Information
18
1513-23
611
2956
English
IJPSR
V Sai Shivram, Swapnil Deshmukh*, Vishal Dalavi and Dipak Sonawane
Research and Development Department, Tulip Lab Pvt Ltd., Ranjangaon, Pune, Maharashtra, India
fnd@tlplindia.com
07 October, 2015
22 February, 2016
09 March, 2016
10.13040/IJPSR.0975-8232.7(4).1513-23
01 April, 2016