Formulation, Optimization and Evaluation of Rimegepant Pulsatile Tablets
for Chronotherapeutic Management of Migraine
Indrayani Satpute; Prof. Vinayak Mundhe
Department of Pharmaceutics, Dr.
Vedprakash Patil Pharmacy College, Chh. Sambhajinagar
*Correspondence: Indrayani.ds2001@gmail.com
DOI: https://doi.org/10.71431/IJRPAS.2026.5715
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Article
Information
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Abstract
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Review Article
Received: 23/07/2026
Accepted: 26/07/2026
Published:31/07/2026
Keywords
Rimegepant; pulsatile tablet; migraine;
chronotherapy; crospovidone; HPMC; ethyl cellulose; experimental design.
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Background: Migraine attacks frequently show circadian
variation, and conventional immediate-release oral dosage forms may not provide
drug exposure at the most therapeutically relevant time. Rimegepant, a
calcitonin gene-related peptide (CGRP) receptor antagonist, is an effective
agent for acute and preventive migraine therapy; however, a programmed oral
delivery system may improve chronotherapeutic targeting. Objective: This
study aimed to formulate, optimize and evaluate rimegepant pulsatile tablets
designed to provide a defined lag phase followed by rapid drug release.
Methods: Tablets were prepared by direct compression using microcrystalline
cellulose, lactose, crospovidone, hydroxypropyl methylcellulose (HPMC), ethyl
cellulose, magnesium stearate and talc. A two-factor, three-level
experimental design was applied to evaluate the influence of crospovidone and
HPMC concentrations on disintegration/lag time and percent drug release.
Preformulation studies, UV spectrophotometric analysis, FTIR, DSC,
precompression evaluation, post-compression testing, in vitro dissolution and
accelerated stability studies were performed. Results: Rimegepant showed
acceptable organoleptic properties, a melting range of 150-153 °C and maximum
absorbance at 260 nm. FTIR and DSC results indicated the absence of major
drug-excipient incompatibility. The prepared batches exhibited
disintegration/lag times ranging from 49 to 80 min and drug release from 70%
to 91%. The optimized formulation F9, containing 24 mg crospovidone, 25 mg
HPMC and 39 mg ethyl cellulose, showed thickness of 2.4 mm, hardness of 2.9
kg/cm², friability of 0.40%, drug content of 99.2%, disintegration/lag time
of 49 min and drug release of 91%. After 3 months of accelerated stability
testing, F9 retained 98.3% drug content and 88% drug release. Conclusion: The
optimized rimegepant pulsatile tablet demonstrated satisfactory pharmaceutical
quality, improved release performance and short-term stability, indicating
its potential for further development as a chronotherapeutic system for
migraine management.
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INTRODUCTION:
Migraine
is a chronic neurological disorder characterized by recurrent attacks of
moderate-to-severe headache, commonly accompanied by nausea, vomiting,
photophobia and phonophobia. Because attacks are often recurrent, unpredictable
and disabling, migraine creates a considerable clinical and socioeconomic
burden. Calcitonin gene-related peptide (CGRP) has a central role in migraine
pathophysiology by contributing to vasodilation, neurogenic inflammation and
pain signaling within the trigeminovascular system [1-3]. Rimegepant is an
orally active small-molecule CGRP receptor antagonist used for the acute and
preventive treatment of migraine. Its non-vasoconstrictive mechanism provides
an important therapeutic advantage, particularly for patients in whom triptan
therapy may be unsuitable [4-6].
Most
conventional oral dosage forms are designed either to release the drug
immediately after administration or to maintain a prolonged release profile.
These approaches may be less suitable for diseases that exhibit predictable
time-dependent symptom patterns. Disorders such as migraine, asthma,
hypertension, arthritis and peptic ulcer disease are influenced by circadian
rhythms, and symptoms may intensify during specific periods of the day. In such
cases, a dosage form that remains relatively inactive for a predetermined lag
period and then releases the drug rapidly can better synchronize drug
availability with the expected period of disease activity [7,8]. Pulsatile drug
delivery systems (PDDS) are therefore intended to provide minimal release
during the lag phase followed by a rapid release pulse. This strategy may
reduce unnecessary drug exposure during symptom-free periods and improve
convenience by decreasing the need for repeated dosing [9-12].
The
development of a rimegepant pulsatile tablet is justified by the circadian
occurrence of migraine attacks in many patients, especially early morning
episodes. A bedtime-administered formulation with programmed release could
provide effective drug levels near the anticipated attack window. Hydrophilic
polymers such as HPMC control water uptake and gel formation, whereas
hydrophobic polymers such as ethyl cellulose reduce penetration of the
dissolution medium and contribute to lag-time control. Crospovidone acts by
swelling and wicking, thereby promoting rapid tablet rupture and drug release once
sufficient hydration has occurred. Hence, optimization of polymer and
superdisintegrant concentrations is essential to achieve a suitable balance
between lag time and burst release [13-17].
Figure 1. Schematic representation of pulsatile drug release after
a programmed lag phase.
Figure 2. CGRP receptor pathway targeted by rimegepant in
migraine therapy.
MATERIALS AND METHODS
Materials
Rimegepant
was used as the active pharmaceutical ingredient. Microcrystalline cellulose
and lactose monohydrate were selected as diluents, crospovidone was used as a
superdisintegrant, HPMC served as the hydrophilic release-retarding polymer,
ethyl cellulose was used as a hydrophobic release modifier, magnesium stearate
was used as a lubricant and talc was used as a glidant/antiadherent. Distilled
water, methanol and phosphate buffer pH 6.8 were used as analytical and
dissolution media. The details of materials, instruments and experimental
conditions were adopted from the thesis experimental work.
Preformulation and analytical
studies
Rimegepant
was evaluated for colour, odour, texture, stickiness and greasiness. Solubility
was determined in distilled water, 0.1 N HCl, phosphate buffer pH 6.8 and
simulated saliva by equilibrating an excess quantity of drug with each medium,
followed by filtration and UV analysis. The melting point was determined by the
capillary method. For UV spectrophotometric analysis, a methanolic solution of
rimegepant was scanned to identify the wavelength of maximum absorbance.
Calibration standards were prepared in the range of 2-10 µg/mL, and absorbance
was recorded at 260 nm.
Table 1. Summary of
preformulation and analytical observations.
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Parameter
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Observation/Result
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Organoleptic
property
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White
to off-white, odorless, fine and non-sticky crystalline powder
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Solubility
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Freely
soluble in distilled water; soluble in pH 6.8 phosphate buffer and simulated
saliva; slightly soluble in 0.1 N HCl
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Melting
range
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Onset
at 150 °C and complete melting at 153 °C
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λmax
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260
nm in methanolic solution
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Calibration
range
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2-10
µg/mL with increasing absorbance from 0.145 to 0.480
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Figure 3. UV spectrum showing the lambda max of rimegepant at
260 nm.
Figure 4. Calibration curve of rimegepant within the selected
analytical range.
Drug-excipient
compatibility studies
Drug-excipient
compatibility was assessed by Fourier-transform infrared (FTIR) spectroscopy
and differential scanning calorimetry (DSC). FTIR spectra of pure rimegepant
and its physical mixture with selected excipients were recorded by the KBr pellet
method over the range of 4000-400 cm⁻¹. Characteristic functional group peaks
were compared for shifts, disappearance or the formation of additional peaks.
DSC analysis was performed for the pure drug and the drug-excipient mixture in
sealed aluminium pans under a nitrogen atmosphere at a heating rate of 10
°C/min over 30-300 °C. Thermal transitions were examined to detect possible
interactions or incompatibility.
Figure 5. FTIR spectra of pure rimegepant and
rimegepant-excipient mixture.
Table 2. FTIR
interpretation of rimegepant.
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Functional group
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Expected peak (cm⁻¹)
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Observed peak (cm⁻¹)
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Inference
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N-H
stretching (amide)
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3300-3400
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3325
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Confirmed
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Aromatic
C-H stretching
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3000-3100
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3050
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Confirmed
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C=O
stretching (amide)
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1650-1700
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1665
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Confirmed
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Aromatic
C=C stretching
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1500-1600
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1580
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Confirmed
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C-N
stretching
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1200-1350
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1250
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Confirmed
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C-F
stretching
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1000-1400
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1100
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Confirmed
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Figure 6. DSC thermograms of pure rimegepant and
rimegepant-excipient mixture.
Table 3. DSC
observations of pure drug and drug-excipient mixture.
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Thermal parameter
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Pure drug
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Drug + excipients
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Onset
temperature (°C)
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143.2
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133.3
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Peak
temperature (°C)
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153.5
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151.9
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Endset
temperature (°C)
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178.4
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172.7
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Enthalpy
ΔH (mJ)
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186.2
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176.7
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Experimental design and formulation development
A
two-factor, three-level experimental design was employed for formulation
optimization. Crospovidone and HPMC were selected as independent variables,
while disintegration/lag time and percent drug release were selected as
dependent responses. Nine formulation batches (F1-F9) were prepared by direct
compression. Rimegepant, diluents and functional excipients were passed through
a suitable sieve and blended by geometric dilution. Crospovidone, HPMC and
ethyl cellulose were incorporated according to the design composition.
Magnesium stearate and talc were added during the final lubrication step and
mixed gently to avoid over-lubrication. The lubricated blend was compressed
into tablets with a target tablet weight as per the formulation design.
Table 4. Formulation
design and main response data.
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Batch
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MCC (mg)
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Crospovidone (mg)
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HPMC (mg)
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Ethyl cellulose (mg)
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Lag time/DT (min)
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Drug release (%)
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F1
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85
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10
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10
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15
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80
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88
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F2
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80
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10
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17
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18
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70
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70
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F3
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75
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10
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25
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21
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60
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85
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F4
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70
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17
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10
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24
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80
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82
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F5
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65
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17
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17
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27
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60
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72
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F6
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60
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17
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25
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30
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65
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78
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F7
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55
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24
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10
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33
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60
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88
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F8
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50
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24
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17
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36
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60
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80
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F9
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45
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24
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25
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39
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49
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91
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Evaluation of powder
blend and tablets
The
powder blends were evaluated for angle of repose, bulk density, tapped density,
Carr’s index and Hausner ratio to determine flowability and compressibility
before compression. The prepared tablets were evaluated for thickness,
hardness, friability, disintegration/lag time, drug content and in vitro
dissolution. Dissolution testing was carried out in phosphate buffer pH 6.8 at
37 ± 0.5 °C. Samples were withdrawn at specified intervals, filtered, diluted
suitably and analysed by UV-visible spectrophotometry. The optimized batch was
subjected to accelerated stability testing for 3 months at 40 ± 2 °C and 75 ±
5% relative humidity, and samples were evaluated at 0, 1, 2 and 3 months.
RESULTS AND DISCUSSION
Preformulation and
analytical suitability
Rimegepant
was observed as a white to off-white, odourless and non-sticky crystalline
powder, confirming that the drug possessed acceptable handling characteristics
for tablet manufacturing. It was freely soluble in distilled water, soluble in
phosphate buffer pH 6.8 and simulated saliva, and slightly soluble in 0.1 N
HCl. The narrow melting range of 150-153 °C indicated satisfactory purity and
the absence of gross thermal instability. The UV spectrum showed maximum
absorbance at 260 nm. The calibration data displayed a proportional increase in
absorbance over the 2-10 µg/mL concentration range, confirming the suitability
of the UV method for routine formulation analysis.
Drug-excipient
compatibility
The
FTIR spectrum of pure rimegepant exhibited characteristic absorption bands
corresponding to N-H stretching, aromatic C-H stretching, amide C=O stretching,
aromatic C=C stretching, C-N stretching and C-F stretching. These
characteristic peaks were retained in the drug-excipient physical mixture,
indicating that no major chemical interaction occurred between rimegepant and
the selected excipients. DSC thermograms further supported compatibility, as
the principal endothermic melting peak of rimegepant was present in both the
pure drug and the physical mixture. The slight shift in peak temperature from
153.5 °C to 151.9 °C and the decrease in enthalpy from 186.2 mJ to 176.7 mJ may
be attributed to dilution, polymer mixing and reduced crystallinity rather than
incompatibility. The absence of additional thermal events confirmed the
suitability of the selected excipients for formulation development.
Effect of formulation
variables
The
prepared formulation batches showed disintegration/lag times between 49 and 80
min, demonstrating that the selected polymer-superdisintegrant system
effectively modulated time-controlled tablet rupture. Crospovidone enhanced
water uptake and internal swelling, which facilitated tablet rupture and
exposure of the drug after the lag period. HPMC contributed to hydration and
gel-barrier formation, thereby influencing medium penetration and controlling
the duration of the lag phase. Ethyl cellulose provided an additional
hydrophobic barrier and supported delayed release. The results indicate that an
appropriate balance among these excipients is required, because excessive
barrier formation may delay drug liberation, whereas adequate crospovidone
content promotes rapid disintegration and post-lag burst release.
The
Design-Expert analysis suggested that a quadratic model was appropriate for
both responses. For disintegration/lag time, the reported model p-value was
0.0003, and the quadratic effect of crospovidone showed a meaningful influence.
For cumulative drug release, the model was significant with a p-value of
0.0367, and the quadratic effect of HPMC was important. The contour and 3D
response surface plots indicated that drug release was maximized near the F9
composition, reflecting an optimized balance between rapid rupture and
controlled barrier formation.
Figure 7. Contour and 3D response surface plots for
disintegration/lag time.
Figure 8. Contour and 3D response surface plots for percent drug
release.
Precompression and
post-compression evaluation
The
powder blends showed acceptable flow and compressibility for direct
compression. Across the formulations, angle of repose values ranged from 27.4°
to 31.5°, bulk density from 0.42 to 0.46 g/cm³, tapped density from 0.51 to
0.53 g/cm³, Carr’s index from 11.53% to 17.64% and Hausner ratio from 1.13 to
1.21. These values indicate good processing behaviour. The optimized batch F9
showed an angle of repose of 28.6°, Carr’s index of 14.55% and Hausner ratio of
1.16, confirming good to excellent flow properties during compression.
Post-compression evaluation
demonstrated that all formulations possessed acceptable physical quality.
Tablet thickness ranged from 2.0 to 3.3 mm, hardness from 1.3 to 2.9 kg/cm² and
friability from 0.40% to 0.72%. The optimized F9 batch produced the most
favourable overall profile, with thickness of 2.4 mm, hardness of 2.9 kg/cm²,
friability of 0.40%, drug content of 99.2%, disintegration/lag time of 49 min
and drug release of 91%. The optimized post-compression parameters are
summarized in Table 6.
Table 5.
Post-compression evaluation of rimegepant pulsatile tablets.
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Batch
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Thickness (mm)
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Hardness (kg/cm²)
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Friability (%)
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Drug content (%)
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Drug release (%)
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F1
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2.0
|
1.6
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0.72
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96.5
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88
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F2
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3.1
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1.7
|
0.68
|
97.0
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70
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F3
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2.9
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1.8
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0.70
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96.8
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85
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F4
|
2.2
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2.0
|
0.65
|
97.5
|
82
|
|
F5
|
2.2
|
1.9
|
0.60
|
98.0
|
72
|
|
F6
|
3.3
|
1.3
|
0.55
|
98.6
|
78
|
|
F7
|
3.1
|
1.7
|
0.48
|
98.2
|
88
|
|
F8
|
3.2
|
2.0
|
0.52
|
97.8
|
80
|
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F9
|
2.4
|
2.9
|
0.40
|
99.2
|
91
|
Table 6. Summary of
post-compression evaluation parameters for optimized batch F9.
|
Evaluation
parameter
|
Test
result (optimized F9)
|
Acceptance
/ requirement
|
Inference
|
|
Average tablet weight / weight variation
|
300 mg; uniform tablet weight
|
Individual tablet weight should
remain within pharmacopoeial variation limit
|
Passed; indicates uniform die
filling and dose consistency
|
|
Thickness
|
2.4 mm
|
Tablets should show uniform
dimensional consistency
|
Passed; suitable handling and
packaging characteristics
|
|
Hardness
|
2.9 kg/cm²
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Adequate strength without
excessive delay in release
|
Passed; excellent mechanical
integrity
|
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Friability
|
0.40%
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NMT 1.0% weight loss
|
Passed; good resistance to
abrasion and handling stress
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Disintegration / lag time
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49 min
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Programmed lag period followed by
rapid release is required for pulsatile delivery
|
Passed; shortest
lag/disintegration time among trial batches
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Drug content
|
99.2%
|
Generally acceptable range:
95-105%
|
Passed; excellent drug uniformity
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In vitro drug release after lag
time
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91%
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High burst release after lag time;
desired release >85-90%
|
Passed; confirms effective
pulsatile release behavior
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Note: NMT = not more than. The
optimized F9 batch complied with the required post-compression quality
attributes, showing adequate mechanical strength, low friability, excellent
drug content uniformity and satisfactory burst release after the programmed lag
period.
Figure 9. Comparative performance of formulation batches F1-F9.
Optimization of
formulation batch F9
Among
the nine trial formulations, F9 was selected as the optimized batch. It
contained 24 mg crospovidone, 25 mg HPMC, 39 mg ethyl cellulose, 45 mg
microcrystalline cellulose and constant quantities of rimegepant, lactose,
magnesium stearate and talc. F9 exhibited the shortest disintegration/lag time
of 49 min and the highest drug release of 91%. This performance can be
attributed to the optimized concentration of crospovidone, which improved
swelling and wicking, together with HPMC and ethyl cellulose levels that
provided sufficient lag-time control without suppressing burst release.
Therefore, the optimized tablet met the intended objective of maintaining an
initial programmed delay followed by rapid drug release.
Stability of optimized
formulation
The
optimized F9 batch remained stable during the 3-month accelerated stability
study. Tablet thickness remained unchanged at 2.4 mm, while weight variation
changed only from 300 to 301 mg. Hardness decreased slightly from 2.9 to 2.7
kg/cm² and friability increased from 0.40% to 0.46%; however, both parameters
remained within acceptable limits. Drug content decreased marginally from 99.2%
to 98.3%, disintegration/lag time increased from 49 to 52 min and drug release
decreased from 91% to 88%. These minor changes indicate preservation of
physical integrity, chemical stability and functional release performance.
Nevertheless, long-term stability studies are required before scale-up,
regulatory evaluation or clinical application.
Table 7. Accelerated
stability data of optimized batch F9.
|
Parameter
|
0 month
|
1 month
|
2 months
|
3 months
|
|
Thickness
(mm)
|
2.4
|
2.4
|
2.4
|
2.4
|
|
Hardness
(kg/cm²)
|
2.9
|
2.8
|
2.8
|
2.7
|
|
Friability
(%)
|
0.40
|
0.42
|
0.44
|
0.46
|
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Weight
variation (mg)
|
300
|
300
|
301
|
301
|
|
Drug
content (%)
|
99.2
|
98.9
|
98.6
|
98.3
|
|
Disintegration/lag
time (min)
|
49
|
50
|
51
|
52
|
|
Drug
release (%)
|
91
|
90
|
89
|
88
|
CONCLUSION
Rimegepant
pulsatile tablets were successfully formulated and evaluated using direct
compression and a two-factor experimental design. Preformulation studies
confirmed the suitability of rimegepant for oral tablet development, while FTIR
and DSC analyses demonstrated compatibility with the selected excipients. The
formulation variables significantly affected both lag time and drug release
behaviour. The optimized F9 batch showed desirable pharmaceutical
characteristics, including thickness of 2.4 mm, hardness of 2.9 kg/cm²,
friability of 0.40%, drug content of 99.2%, disintegration/lag time of 49 min
and drug release of 91%. Accelerated stability testing confirmed that F9
maintained acceptable physical, chemical and release characteristics over 3
months. The optimized formulation may therefore represent a promising
chronotherapeutic platform for migraine management, particularly for patients
with predictable attack patterns. Further studies should include long-term
stability testing, pharmacokinetic evaluation, in vivo chronotherapeutic
correlation and scale-up assessment.
ACKNOWLEDGEMENT
The
author gratefully acknowledges the guidance, laboratory assistance and
institutional facilities provided during the formulation and evaluation work.
This manuscript was prepared using data generated from the submitted thesis.
CONFLICTS OF INTEREST
The
author declares that there is no conflict of interest.
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