Influence Of Formulation Variables Research Articles

Influence of formulation variables on the processability and properties of tablets manufactured by fused deposition modelling

The present work studied the influence of different formulation variables (defined also as factors), namely, different polymers (HPC EF, PVA and HPMC-AS LG), drugs with different water solubilities (paracetamol, hydrochlorothiazide and celecoxib) and drug loads (10 or 30 %) on their processability by HME and FDM. Both filaments and tablets were characterized for physic and chemical properties (DSC, XRPD, FTIR) and performance properties (drug content, in vitro drug release). Experiments were designed to highlight relationships between the 3 factors selected and the mechanical properties of filaments, tablet mass and dissolution profiles of the model drugs from printed tablets. While the combination of hydrochlorothiazide and HPMC-AS LG could not be extruded, the combination of paracetamol with HPC EF turned the filaments too ductile and not stiff enough hampering the process of printing. All other polymer and drug combinations could be successfully extruded and printed. Models reflected the influence of the solubility of the drug considered but not the drug load in formulations. The ranking of the drug release rates was in good agreement with their solubilities. Furthermore, PVA presenting the fastest swelling rate, promoted the fastest drugs’ releases in comparison with the other polymers studied. Overall, the study enabled the identification of the key factors affecting the properties of printed tablets, with the proposal of a model that has valued the relative contribution of each factor to the overall performance of tablets.

Formulation Optimization and Characterization of Spray-Dried Medium Chain Triglycerides-Rich Oil

Medium chain triglycerides (MCT) are important substrates of the energy metabolism and anabolic processes in mammals. In this study, MCT-rich oil was encapsulated in the mixing ratios of maltodextrin and protein by spray drying to produce spray-dried MCT-rich oil (SMCT). Spray-dried conditions were an inlet temperature of 200 °C, an outlet temperature of 90 °C, and a flow rate of 0.70 L/h. Box–Behnken experimental design and response surface methodology were applied for modeling the influence of formulation variables on powder recovery of SMCT. The key variables were concentration of maltodextrin (10-30% W/W), total protein (5–15% w/w), and MCT-rich oil (5–15% w/w). The microparticles were characterized in terms of particle morphology, yield, Carr's index, moisture content, flowability, hygroscopicity, and powder diffraction. The highest yield of SMCT was 41.19% obtained under the optimized conditions (maltodextrin concentration of 15% w/w, total protein concentration of 8% w/w, MCT-rich oil concentration of 15%). Experimentally obtained values were consistent with those predicted by the model, indicating the suitability of the employed model and the success of the model in optimizing the formulation.

Formulation, characterization and statistical optimization of enalapril-loaded lipospheres

Lipid-based polymers have been proved efficient drug carriers for overcoming the insufficiencies of conventional formulations. Ceresin wax was employed to improve permeability, oral bioavailability and patient compliance by preparing enalapril (EP)-loaded lipospheres with a simple solvent evaporation method. A Box–Behnken design with the proposed polynomial equations and quadratic model was applied to investigate and statistically validate the collective influence of formulation variables on lipospheres. Spherical smooth-surfaced lipospheres with an average size of 55 μm with excellent micromeritic properties were produced. Differential scanning calorimetry, X-ray diffraction and Fourier transmission infrared spectroscopy findings proved the lack of any possible interaction between formulation components. The zeta potential ranged from −5 to −20 mV, suggesting the significant stability of lipospheres. Responses such as percentage yield (29–68%), entrapment efficiency (21–53%) and drug release (42–93%) were found to be affected greatly by the concentrations of lipids and the surfactant, and the stirring speed. Reduced and sustained EP release from lipospheres may lower treatment cost and enhance hypertensive patients’ compliance.

Influence of formulation variables on miconazole nitrate–loaded lipid based nanocarrier for topical delivery

The purpose of this study was to develop miconazole nitrate (MN) based solid lipid nano-carrier formulae for topical delivery to enhance its antifungal effectiveness.Miconazole nitrate loaded Solid lipid nanoparticles (MN-SLNs) were formulated using a high shear homogenization technique characterized by particle size, polydispersity index (PI), trapping efficiency (EE percent), drug loading (DL percent) and zeta potential (ZP) characteristics. Furthermore, the optimized formulae were investigated for in-vitro release, ex-vivo study, skin toxicity test, and antifungal activity.With a particle size range of 244.2 ± 27.2 nm to 493.6 ± 35.3 nm, the selected MN-SLNs were spherical shaped. A high EE product percentage ranging from 79.38 ± 2.35 percent to 95.92 ± 6.12 percent and Zeta potential ZP values ranging from-21.6 ± 7.05 mV to-31.4 ± 6.84 mV suggesting strong stability was achieved. A controlled release of MN from the SLNs up to 48 h was shown in-vitro release study. The ex-vivo study showed that the selected MN-SLN (F4) mixture exhibited higher MN flux in the skin than a 1% MN solution. Moreover, selected MN-SLN (F4) has demonstrated a higher zone of inhibition against Candida albicans than a simple drug solution. MN-SLN (F4) had the lowest toxicity value for the skin. Besides, the MN-SLNs (F4) substantially reported antifungal activity with the least histopathological improvements compared to MN-solution utilizing immune-suppressing albino rats with induced candidiasis fungal infection.It can be fulfilled that SLNs can be acquired as a promising carrier for topical delivery of poorly soluble MN.

DEVELOPMENT OF ZOLMITRIPTAN MOUTH DISSOLVING FILMS: FORMULATION VARIABLES, MECHANICAL PROPERTIES, AND IN VITRO DRUG RELEASE STUDIES

Objective: The objective of the present investigation is to prepare zolmitriptan (ZOL) mouth dissolving films (MDFs) and to investigate the influence of formulation variables on physicomechanical, chemical, and drug release properties of the prepared MDFs.
 Methods: The MDFs were prepared by solvent casting technique using wet film applicator. The impact of hydroxypropyl methylcellulose of different viscosity grades (hydroxy propyl methyl cellulose [HPMC] E3, E5, and E15), plasticizers (glycerol and polyethylene glycol [PEG]-400), and solubilizing agents (polyvinyl pyrrolidone [PVP K30] and sodium lauryl sulfate [SLS]) on physicomechanical, chemical, and drug release properties were evaluated. The MDFs were also characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffractometry studies.
 Results: The MDFs prepared were transparent and smooth and showed no recrystallization. The tensile strength of the MDFs increased significantly with an increase in polymer viscosities, and about a 2.63-fold increase in tensile strength was observed for HPMC E15 MDFs compared to E3, whereas an increase in film thickness resulted in brittle MDFs with low tensile strength. Similar results were observed with percent elongation and folding endurance of the MDFs. In vitro, drug release studies indicate that higher film thickness and polymer viscosities delayed the MDF disintegration and, in turn, the ZOL release. Addition of PVP K30 and SLS to HPMC E3 formulations resulted in 1.66- and 1.53-fold increase in ZOL release rates.
 Conclusion: Overall, F7 formulation showed quicker disintegration (within 11 s) and ZOL release rates (within 180 s) along with good physicomechanical properties. These results indicated that the disintegration and drug release of ZOL can be enhanced to a greater extent by optimizing formulation variables in MDFs.

Transdermal delivery of fluvastatin sodium via tailored spanlastic nanovesicles: mitigated Freund's adjuvant-induced rheumatoid arthritis in rats through suppressing p38 MAPK signaling pathway

The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (24). Applying Design-Expert® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm2). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.

Preparation and evaluation of famotidine nanosuspension

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. There are many methods used to increase dissolution rate of drug and in this study, the dissolution of the drug was enhanced by the preparation of nanosuspension. Famotidine nanosuspension was prepared by antisolvent precipitation method, where famotidine dissolved in methanol at room temperature and emptied into water containing different types of stabilizers (single and in combination). The optimum formula (F9) was selected according to particle size (362.8nm) and release profile (80 % of drug release within the 10 minutes) in comparison to pure famotidine powder release. The influence of formulation variables like the type and concentration of stabilizers Polyvinyl pyrrolidone K30, polyvinyl alcohol and poloxamer 188 (PVP K-30, PVA and poloxamer 188) in addition to combination of stabilizers on particle size of drug nanosuspensions were studied. The result showed that single stabilizer (poloxamer 188) has perfect surface affinity and could form a substantial mechanical and thermodynamic barrier at the interface of dug molecule. As the concentration of stabilizer increases the particle size decreases at fixed drug concentration (drug: stabilizer ratio 1:2).

Preparation and evaluation of famotidine nanosuspension

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. There are many methods used to increase dissolution rate of drug and in this study, the dissolution of the drug was enhanced by the preparation of nanosuspension. Famotidine nanosuspension was prepared by antisolvent precipitation method, where famotidine dissolved in methanol at room temperature and emptied into water containing different types of stabilizers (single and in combination). The optimum formula (F9) was selected according to particle size (362.8nm) and release profile (80 % of drug release within the 10 minutes) in comparison to pure famotidine powder release. The influence of formulation variables like the type and concentration of stabilizers Polyvinyl pyrrolidone K30, polyvinyl alcohol and poloxamer 188 (PVP K-30, PVA and poloxamer 188) in addition to combination of stabilizers on particle size of drug nanosuspensions were studied. The result showed that single stabilizer (poloxamer 188) has perfect surface affinity and could form a substantial mechanical and thermodynamic barrier at the interface of dug molecule. As the concentration of stabilizer increases the particle size decreases at fixed drug concentration (drug: stabilizer ratio 1:2).

Preparation and evaluation of famotidine nanosuspension

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. There are many methods used to increase dissolution rate of drug and in this study, the dissolution of the drug was enhanced by the preparation of nanosuspension. Famotidine nanosuspension was prepared by antisolvent precipitation method, where famotidine dissolved in methanol at room temperature and emptied into water containing different types of stabilizers (single and in combination). The optimum formula (F9) was selected according to particle size (362.8nm) and release profile (80 % of drug release within the 10 minutes) in comparison to pure famotidine powder release. The influence of formulation variables like the type and concentration of stabilizers Polyvinyl pyrrolidone K30, polyvinyl alcohol and poloxamer 188 (PVP K-30, PVA and poloxamer 188) in addition to combination of stabilizers on particle size of drug nanosuspensions were studied. The result showed that single stabilizer (poloxamer 188) has perfect surface affinity and could form a substantial mechanical and thermodynamic barrier at the interface of dug molecule. As the concentration of stabilizer increases the particle size decreases at fixed drug concentration (drug: stabilizer ratio 1:2).

ARTEMETHER LOADED ETHYLCELLULOSE NANOSUSPENSIONS: EFFECTS OF FORMULATION VARIABLES, PHYSICAL STABILITY AND DRUG RELEASE PROFILE

Objective: The aim of this study was to explore the individual and joint effects of drug: ethylcellulose ratio, content of tween 80 and chloroform: water volume ratio on particles' size and size distribution of artemether loaded ethyl cellulose nanosuspension formulations, aiming to achieve nanosuspension with desired particles properties, stability and drug release profile.Methods: Mixed levels design was used to generate a series of artemether loaded ethylcellulose nanosuspensions that produced by emulsification-solvent evaporation technique. Formulations were qualified for particle size and size distribution using dynamic light scattering technique. Best ranked formulation was then evaluated for stability and drug release rate and kinetics.Results: Drug: polymer ratio, content of surfactant and organic: water volume ratio were found to exert considerable influences (p<0.05) on particle size of produced nanosuspensions, either individually or as joint variables. Peak intensity property of nanosuspensions was found to be influenced by drug: polymer ratio (p<0.05) whereas the influences of different variables on the polydisperse index property appear inconsequential (p>0.05). Best ranked (optimal) artemether nanosuspension proved stable and capable to improve and maintain the release of loaded drug over 24 h, at least under the setting conditions of this study.Conclusion: Focusing on both the individual and joint influences of formulation variables assist in achieving nanosuspension with desired particles characteristics, stability and drug release profile.

Formulation and evaluation of injectable in situ forming microparticles for sustained delivery of lornoxicam

The objective of this study is to formulate biodegradable in situ microparticles (ISM) containing lornoxicam for post-operative and arthritic pain management. ISM emulsions were prepared according to 25 full factorial experimental design to investigate the influence of formulation variables on the release profile of the drug. The independent variables studied are the polymer type, polymer inherent viscosity, polymer concentration, oil type and polymer:oil ratio. In vitro drug release, microscopical examination, particle size determination and syringeability measurement were selected as dependent variables. The effect of γ-sterilization on the prepared formulae was also examined. The prepared formulae showed extended drug release over two weeks, and flow time below 5 s/ml. Scanning electron microscope revealed that the prepared microparticles were spherical in shape, with diameter ranging from 3.45 to 22.78 µm. In vivo pharmacokinetic evaluation of two selected optimum formulations in rabbits showed prolonged drug absorption indicated by delayed Tmax and the extended mean residence time. In conclusion, the prepared injectable ISM could be a promising approach for providing extended delivery of lornoxicam with low initial burst effect.

Influence of the Component Excipients on the Quality and Functionality of a Transdermal Film Formulation.

The influence of formulation variables, i.e., a hydrophilic polymer (Methocel(®) E15) and a film-forming polymer (Eudragit(®) RL 100 and Eudragit(®) RS 100), on the physicochemical and functional properties of a transdermal film formulation was assessed. Several terpenes were initially evaluated for their drug permeation enhancement effects on the transdermal film formulations. D-Limonene was found to be the most efficient permeation enhancer among the tested terpenes. Transdermal film formulations containing granisetron (GRN) as a model drug, D-limonene as a permeation enhancer, and different ratios of a hydrophilic polymer (Methocel(®) E15) and a film-forming polymer (Eudragit(®) RL 100 or Eudragit(®) RS 100) were prepared. The prepared films were evaluated for their physicochemical properties such as weight variation, thickness, tensile strength, folding endurance, elongation (%), flatness, moisture content, moisture uptake, and the drug content uniformity. The films were also evaluated for the in vitro drug release and ex vivo drug permeation. The increasing ratios of Methocel(®):Eudragit(®) polymers in the formulation linearly and significantly increased the moisture content, moisture uptake, water vapor transmission rate (WVTR), and the transdermal flux of GRN from the film formulations. Increasing levels of Methocel(®) in the formulations also increased the rate and extent of the GRN release and the GRN permeation from the prepared films.

Development of a poly (ɛ Caprolactone) based nanoparticles for oral delivery of Quercetin

Quercetin loaded Poly (ɛ caprolactone; PCL) nanoparticles were prepared by the solvent displacement method. The influences of formulation variables (polymer and surfactant concentration) were investigated. The results of formulations F1-F9 showed Particle size (nm) in a different medium ranged from 189.10 ± 0.28 to 252.14 ± 2.32 in 0.1 N HCl and 184.06 ± 3.84 to 288.54 ± 2.86 in phosphate buffer pH 7.4, Dissolution efficiency (%) of 46.42 ± 5.42 to 72.20 ± 0.68 and drug loading (%) of 7.18 ± 0.25 to 9.27 ± 0.50. High Resolution-Transmission Electron Microscopy image represents the spherical and smooth surface of nanoparticles. The results suggested that, quercetin loaded polymeric nanoparticles may be the viable strategy for controlled release for more than 48 hours, and improves the physical stability of quercetin.

Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application

The objective of this research work was to design, develop and optimize the self micro-emulsifying drug delivery system (SMEDDS) of Felodipine (FL) filled in hard gelatine capsule coated with polymer in order to achieve rapid drug release after a desired time lag in the management of hypertension. Microemulsion is composed of a FL, Lauroglycol FCC, Transcutol P and Cremophor EL. The optimum surfactant to co-surfactant ratio was found to be 2:1. The resultant microemulsions have a particle size in the range of 65-85 nm and zeta potential value of -13.71 mV. FL release was adequately adjusted by using pH independent polymer i.e. ethyl cellulose along with dibutyl phthalate as plasticizer. Influence of formulation variables like viscosity of polymer, type of plasticizer and percent coating weight gain was investigated to characterize the time lag. The developed formulation of FL SMEDDS capsules coated with ethyl cellulose showed time lag of 5-7 h which is desirable for chronotherapeutic application.

Influence of Formulation Variables and Process Parameters on the Release Performance of Cefpodoxime Proxetil from Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose-Alginate Based Matrices

Influence of Formulation Variables and Process Parameters on the Release Performance of Cefpodoxime Proxetil from Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose-Alginate Based Matrices

Felodipine β-cyclodextrin complex as an active core for time delayed chronotherapeutic treatment of hypertension

The present research work deals with the development of a time delayed chronotherapeutic formulation of felodipine (FD) aimed at rapid drug release after a desired lag time in the management of hypertension. The developed system comprises a drug core embedded within a swellable layer and coated with an insoluble, water permeable polymeric system. FD cyclodextrin complex was used as an active core while ethyl cellulose was used as an effective coating layer. Dissolution studies of the complex revealed that there was a 3-fold increase in dissolution of the complex compared to plain FD. This dissolution enhancement and rapid drug release resulted from FD amorphisation, as confirmed by XRD, DSC and SEM studies. FTIR and ¹H NMR studies confirmed the complex formation between FD and cyclodextrin based on the observed hydrogen bond interactions. FD release was adequately adjusted by using a pH independent polymer, i.e., ethyl cellulose, along with dibutyl phthalate as plasticizer. Influence of formulation variables like polymer viscosity, plasticizer concentration, super disintegrant concentration in the swellable layer and percent coating weight gain was investigated to characterize the lag time. Upon permeation of water, the core tablet swelled, resulting in the rupture of the coating layer, followed by rapid drug release. The developed formulation of FD showed a lag time of 5-7 h, which is desirable for chronotherapeutic application.

Development and evaluation of a novel pellet-based tablet system for potential colon delivery of budesonide.

Budesonide, a potent glucocorticoid, is used for the treatment of inflammatory bowel diseases. Current available oral formulations of budesonide have low efficacy against ulcerative colitis because of the premature drug release in the upper part of the gastrointestinal tract. In this paper a pH- and time-controlled colon-targeted pellet-based tablet of budesonide was established. Pellet cores were prepared by extrusion-spheronization method and further coated with xanthan gum (barrier layer), Eudragit NE30D and L30D55 combination (inner layer), and Eudragit FS30 (as enteric layer) sequentially to achieve the required release profile. The coated pellets then compressed into tablets using inert tabletting granules of Cellactose or Pearlitol. Release studies, performed in simulated gastric, intestinal, and colon pH were used in sequence to mimic the gastrointestinal transit. The influence of formulation variables like barrier layer thickness, inner layer composition, and enteric coat thickness on drug release were investigated and the coated pellets that contained 12% weight gain in xanthan gum layer, Eudragit L30D55 and Eudragit NE30D with a ratio of 3 : 7 in inner layer with 30% weight gain and 25% weight gain in Eudragit FS layer were found to protect the drug release in stomach and small intestine and 83.35 ± 2.4 of budesonide was released at 24 h. The drug release from the tablets prepared using 40% Cellactose 80 as tableting excipient was found to be closely similar to that of uncompressed pellets.

Formulation development of physiological environment responsive periodontal drug delivery system for local delviery of metronidazole benzoate

The objective of the present investigation was to develop and evaluate physiological environment responsive periodontal drug delivery system (PERPDDS) for local delivery of metronidazole benzoate. Poly-ϵ-caprolactone an in situ precipitating polymer was used in combination with, carbopol 934P, a pH simulative polymer to develop PERPDDS. The prepared PERPDDS was evaluated for various parameters such as in vitro gelling capacity, viscosity, rheology, compatibility study, and in vitro diffusion study. A 32 full factorial design was used to investigate the influence of formulation variables. Drug release data from all formulations were fitted to different kinetic models and the korsemeyer-peppas model was found the best fit model. The value of diffusional exponent (n) was in between 0.3283 and 0.3979 indicating purely fickian diffusion release mechanism. Increasing the concentration of each polymeric component increases viscosity, and time for 50% and 90% drug release was observed and graphically represented by the surface response and contour plots.

Formulation and Pharmacokinetics of Diclofenac Lipid Nanoemulsions for Parenteral Application

The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using high-performance liquid chromatography. The drug release from preparation was carried out in phosphate-buffered saline pH 7.4. The cumulative amount of drug released was estimated using a spectrophotometer. The time course of the released drug in rat serum was determined. Diclofenac concentrations from lipid nanoemulsions were higher than that of Voveran injection (solution form) in serum.

Influence of formulation variables in transdermal drug delivery system containing zolmitriptan

The effects of different formulation variables including pressure sensitive adhesive (PSA), thickness of the matrix, solvent system, inclusion of crystallization inhibitor, loading amount of drug and enhancers on the transdermal absorption of zolmitriptan were investigated. Acrylic adhesive with hydroxyl functional group provided good adhesion force and high flux of zolmitriptan. Pseudopolymorphs of zolmitriptan were found to possess different solid-state properties that affected the permeation rate. Polyoxyethylene alkyl ethers significantly increased the permeation of zolmitriptan through hairless mouse skin. However, these enhancers induced crystallization of zolmitriptan. Kollidon ® 30 delayed the crystallization without altering the permeation profile of zolmitriptan. Stability studies suggested that terpenes did not induce crystallization of zolmitriptan in the patch and stable formulations could be produced by using cineole and limonene, or their combination.