Design and Development of Cyclobenzaprine HCl Sustained Release Pellets by Wurster Coating Method

Introduction

Cyclobenzaprine hydrochloride, a skeletal muscle relaxant reduces localized muscle spasms without impairing muscle function. It is a tricyclic amine salt with white crystals. It is readily soluble in water and alcohol, only sporadically soluble in isopropanol, and insoluble in solvents that include hydrocarbons. Cyclobenzaprine works centrally, probably at the level of brain stem to reduce muscle spasm rather than immediately acting on the neuromuscular junction or the muscle. Inhibiting the activity of descending serotonergic neurons, Cyclobenzaprine, a 5HT2 receptor antagonist, decreases muscular tone by binding to the serotonin receptor.

By virtue of their pharmacologic characteristics, skeletal muscle relaxants can be either antispasmodic or antispastic. The anti-spasticity drugs are used to lessen spasticity that interferes with function or daily living tasks, such as in cerebral palsy, multiple sclerosis, and spinal cord injuries. Unknown is how these agents work, i.e., their mechanism of action. By preventing the sarcoplasmic reticulum release of calcium, which prevents muscular contraction, dantrolene directly affects skeletal muscle. Musculoskeletal pain is treated using skeletal muscle relaxant with antispastic. The tricyclic antidepressants and cyclobenzaprine share structural similarities. Pellets for the sustained release of Cyclobenzaprine hydrochloride are made using the Wurster coating method, releasing the medication gradually over an extended period of time and this involves two steps - polymer coating and drug coating.^1-4 The drug in suspension form is applied to dummy pellets during the drug coating process, dried, and sieved. Drug coated pellets are coated with sustained release (SR) polymer to form SR pellets.^5,6 Conventional dosage form typically causes undesired toxicity and ineffectiveness by causing wide-ranging fluctuations in drug concentration in the blood and tissues if the dosage frequency is reduced or increased.⁷

Materials and Methods

The Wurster coating process was used to create pellets for the sustained release of Cyclobenzaprine hydrochloride, which releases the medicine slowly over an extended period of time. The process for making Cyclobenzaprine hydrochloride SR pellets involves two steps - polymer coating and drug coating. In the drug coating procedure,the medication was applied to dummy pellets in suspension form, dried and sieved.^8-10 With SR polymer, drug coated pellets were coated.^11,12 The SR pellets were then sieved, dried, and sent to quality control.

Preformulation Studies⁸

Preformulation activities include everything from assisting in the discovery of new active agents to describing physical characteristic required for the creation of dosage form. Preformulation information that is crucial can speed up and improve the launch of novel medicinal entities for human use. Examination of a drug substance’s physical and chemical characteristics, both by itself and in combination with excipients is known as ‘Preformulation testing’. The sensible development of a dosage form begins with this. The purpose of Preformulation testing is to produce data that can aid in creating a formulation that is stable and bioavailable. Additionally, the employment of Preformulation parameters maximize the likelihood of producing a product that is acceptable, safe, effective, and stable.

Active Pharmaceutical Ingredient (API) Characterisation

1. Physical appearance

2. Solubility

3. Determination of bulk density and tapped density

4. Compressibility index

5. Melting point

6. Loss on drying

Physical appearance

A tiny amount of Cyclobenzaprine HCl powder was placed on a butter paper and examined in a well-lit area. Finally, the texture, colour, and smell were noted.

Solubility

A modest incremental amount of solvent (5 mL) was added to the test tube holding a set quantity of solute (5 mL) or vice versa, to determine the solubility in a semi-quantitative manner. The system was forcefully agitated and visually inspected for any undissolved solute particles after each addition. The ratio of solute to solvent was used to express solubility.

Determination of bulk density and tapped density

This is a measurement used to define particle packing and to precisely calculate how much drug is present in a volume before and after tapping.

Compressibility index

Using the powder density as a starting point, the compressibility was determined.

% Compressibility = Pt-Po X 100

Pt

Where, Pt = Tapped density

Po=Bulk density

Melting point

Using programmable melting point equipment, the melting point of Cyclobenzaprine HCl was determined by capillary method.

Drug Excipient Compatibility Studies^12,13

Studies on drug excipient compatibility were conducted to examine potential interactions between Cyclobenzaprine HCl and other inactive components in the formulation.

Procedure

The compatibility investigation was conducted at 40 o C /75% Relative Humidity (RH) for 0, 2 and 4 weeks, whereas the control samples were held at 2-8 o C. They were examined from a physical and chemical stand point.

Evaluation Parameters

A) Physical Evaluation

1) Angle of repose

Angle of repose was used to assess the flow characteristics of pellets, granules and powders. Pouring the powder into a conical heap on a level, flat surface and measuring the included angle with the horizontal is how the angle of repose is calculated.

Tan-1(2h/d), Where h, is the height of the pile of powder and d is the diameter.

2) Bulk density

Depending on the procedure used for crystallization, grinding, or formulation, a compounds’ bulk density might vary significantly. Bulk density was calculated by pouring pre-separated granules through a large funnel into a graduated cylinder, weighing and measuring the volume.

3) Tapped density

Tapped density was calculated using a mechanical tapper apparatus that was run for a set number of taps until the powder bed volume reached a minimum volume. The mechanical tapper apparatus was placed in a graduated cylinder with a known mass of granules.

4) Carr’s index

The values of bulk density and tapped density was used to calculate Carr’s index.

5) Moisture content

About 50 to 60 mL of methanol was placed in the Karl Fischer titration vessel, and the endpoint should reach using the Karl Fischer reagent. The pellets were pulverized to a fine powder in a dry mortar. The sample was weighed precisely at 0.5 g, and rapidly transferred to the titration tank. Sample was stirred to dissolve it and then titrated with Karl Fischer reagent until the desired result was reached.

B) Chemical Evaluation

1) Assay

Standard preparation

100 mg of Cyclobenzaprine HCl working standard was weighed accurately into a volumetric flask, 50 mL of methanol was added, shaken vigorously, and sonicated before dilution to volume with the methanol. Two mL of this solution was pipetted and added to a 100 mL volumetric flask, diluted to volume with DM water, and then thoroughly mixed.

Sample preparation

In a 100 mL volumetric flask, around 100 mg of drug equivalent pellets were accurately weighed.^9,10 50 mL of methanol was added, sonicated for 10 minutes, chilled and then diluted to volume with methanol. Then 2 mL of the filtrate was added to a 100 mL volumetric flask and diluted to attain the volume.

Procedure

Absorbance was measured of the standard and sample at 271 nm by scanning the solution of the two preparations against blank preparations between 200 and 400 nm.

Dissolution

In each of the six dissolution flasks containing 900 mL of 0.1N HCl, the pellets each equalling 100 mg of cyclobenzaprine was weighed and transferred. The temperature was previously adjusted to 37 o C and 0.50 o C, samples were then collected for the first two hours, then the medium was changed to phosphate buffer 6.8, and further samples were collected for the following 20 hours from a zone that was halfway between the medium’s surface and the top of the rotating blade and not less than 1cm from the vessel wall. The sample was then filtered through a 0.45-mm membrane filter, with the first 4 mL discarded. At 271 nm, the absorbance was determined using a spectrophotometer.

Evaluation of capsules^14,15

1. Uniformity of weight

The average weight of 20 capsules was calculated after carefully weighing them. Following this, each pill was weighed separately. Once the capsule was totally empty, it was cleaned with a brush, and weighed individually to preserve the identification of the shell. The content of the capsule was determined by the weight difference between the capsules and its empty shell. The consistency of the capsules’ weight was estimated using the following formulas. The average net weight was determined from the sum of the individual net weights. The percentage deviation from the average net weight of each capsule was determined. The average net weight of capsule is less than 300 mg, deviation % should be in between ±10 to 20, 80 mg to 150 mg ± 7.5 to 15, more than 250 mg ±5 to 10.

2. Lock length

Locked length is the length of the finished capsule. The listed diameter measurement is the larger cap part, which is most important in making size determinations in the market. Vernier calipers were used to measure it.

Scanning Electron Microscope (SEM analysis)

Hitachi (Model: S-3400 N, Japan) employed SEM analysis to examine the morphology of manufactured pellets without any coating. The SEM photomicrograph of the pellets showed that they were having a rough surface and were spherical in shape.

Results

Fourier-transform infrared spectroscopy (FT-IR) Spectrum

The FT-IR spectra of pure HCL and F5 formulation of Cyclobenzaprine were recorded. FT-IR was used to confirm that the formulations, formulation F5 contained Cyclobenzaprine HCL. There was no overt medication interaction found. These peaks were present in both formulation F6 and pure Cyclobenzaprine HCL, demonstrating no evidence of chemical reaction between the two substances. Additionally, it verified the drug’s stability during formulation.

Discussion

The present work aimed at developing SR pellets of Cyclobenzaprine HCl by Wurster process. FTIR studies showed no unacceptable extra peaks which confirm the absence of chemical interaction between the drug and polymer. Angle of repose, tapped density, bulk density values for the formulations were within the range which indicates that pellets prepared by Wurster process were satisfactory for further studies. The percentage drug content of Cyclobenzaprine was determined by extraction with methanol and analysed by using UV-visible spectrophotometer at 290 nm. After 12th hour, the percentage drug release from all the formulations were recorded as 89.6%, 87.4%, 85.8%, 85.6%, 83.9%, 75.1% for the formulations containing EC N14 2.5%, 5%, 7.5% and EC N50 10%, 12.5% and 15%, respectively. The burst release of Cyclobenzaprine HCl from formulations with EC N50 was comparatively lower than the one with EC N14, due to the fact that EC N50 is more viscous and release retarding capacity is more when compared to EC N14. Formulation F5 was identified to be the best as it matched well with the innovator (F2 = 71).

Conclusion

The study aimed to produce stable Cyclobenzaprine HCl pellets using Wurster pelletizing technique. The results showed that the pellets produced had low moisture content indicating that the layering procedures and raw materials were adequate for producing stable pellets. The pellets exhibited good flow qualities, with an angle of repose within the range of 25-30o , and had a low friability of 0.26%. The tap density of the pellets was between 0.75 and 0.9 g/mL, making them suitable for filling in empty hard gelatin capsule shells. The surface structure of the pellets was smooth, and SEM analyses revealed a homogeneous coating of SR polymer. The percentage medication content for each formulation was within the range of 100-+5%, and the percentage drug release after 12 hours varied between 75.1% and 89.6% depending on the formulation. The study concluded that the chosen formulation, F5, was the best due to its superior compatibility with the innovator and high drug release rate.

Conflict of Interest

Nil