Discriminating Dissolution Method Research Articles

Supercritical enhanced atomization induced particle entrapment for continuous production of injectable micro and nano-suspensions

The production of micro- and nanosized dry powder formulations of pharmaceutical drugs by spraying methods with high yields and desired rheological characteristics is typically challenging from laboratory up to commercial scales. In this work, supercritical CO2 was used in a supercritical enhanced atomization (SEA) process as a bottom-up method to create micro- and nanoparticles, with an enhanced control over their physicochemical properties, to produce injectable aqueous suspensions of itraconazole (ITZ). The existing drying chamber design was optimized to significantly improve the SEA process product yield. Additionally, a novel set-up was integrated for the continuous production of ITZ particles directly collected in an aqueous stabilizer media by the supercritical enhanced atomization-induced particle entrapment into suspension (SEA-PES) process. To evaluate the influence of various SEA-PES processing parameters on the particle size, morphology, residual solvent, and particle collection yield of each experimental run utilising the in-house built continuous set-up, a solvent screening study followed by a design of experiments (DoE) was carried out. Based on the given output parameters, tetrahydrofuran (THF) was selected as the optimum solvent for ITZ. The best excipient/s for stabilising ITZ micro- and nanoparticles in suspension, respectively, have previously been discovered to be vitamin E TPGS (0.5% w/w) in combination with PVP K30 (0.5% w/w). Using both the SEA and SEA-PES methods, homogeneous ITZ micro- and nanosuspensions (solid content of 200 mg/g) with D50 0.23 ± 0.06 μm and 3.5 ± 0.2 μm were produced, respectively. These suspensions were stable and resuspendable after 365 days of storage at 25 °C. Finally, utilising a newly developed discriminatory dissolution method, the in vitro release characteristics of ITZ micro- and nanosuspensions were evaluated. There was no significant difference between the SEA and SEA-PES methods to generate the drug micro- and nanosuspensions, according to both solid-state and in vitro release profiles analysis. This work provides proof of concept for establishing a cost-effective experimental platform for the continuous production of injectable micro-and nanosuspensions of ITZ.

DEVELOPMENT OF A DISCRIMINATORY METHOD FOR DETERMINATION OF IN VITRO DISSOLUTION OF CILNIDIPINE

Objectives: This study involves the development of a discriminatory method to differentiate the in vitro dissolution of cilnidipine’s mouth-dispersing film from that of a commercial tablet. Methods: The mouth-dispersing film was initially developed using a reported established method. A discriminatory dissolution method was developed to assess the in vitro dissolution of the mouth-dispersing film and compare the same with that of the commercial tablet. Results: The study findings indicated the method employed was able to differentiate the dissolution of the fast-dissolving film from the commercial tablet. About 98.52±0.60% of the drug was found to be released from the oral film in 40 min whereas the tablet took nearly 5 h for 92.06±0.49% of the drug to get released. Conclusion: These results demonstrate that the dissolution media identified was able to create the necessary sink condition that would be able to differentiate the dissolution profile of the mouth-dispersing film from the conventional tablet. The ultrasound spectrophotometric method employed was found to be simple rapid and sensitive enough to estimate the drug release from diverse pharmaceutical dosage forms.

Development and validation of a discriminatory dissolution method for amorphous solid dispersion formulation of polymorphic Artemether

The aim of this study was to develop and validate one discriminatory dissolution method for evaluation of amorphous solid dispersion of Artemether in its fixed dose combination (FDC) of Artemether lumefantrine tablets. Methods: The evaluation of discriminatory power of the selected dissolution method was based on saturation solubility and sink condition. The impact of addition of surfactant was evaluated in the selected dissolution method comparing the dissolution rate of Artemether from immediate release Artemether and lumefantrine tablets. Comparative dissolution profile of Artemether from conventional immediate release tablet and solid dispersion tablets were compared using the selected discriminatory dissolution method. The resulting final dissolution method was validated for linearity, precision, robustness and solution stability inline with ICH. Phosphate buffer pH 6.8 (without any surfactant) was finalized as the discriminatory dissolution method based on the comparative dissolution profile between conventional Artemether tablets and Artemether tablets prepared with solid dispersion technology. The proposed analytical method was capable to discriminate different formulation of Artemether .HPLC method with UV detection at wavelengths of 216 nm was followed.The method was found to be linear (R2=0.9998) over a range of 80-120 % of analyte target.The results for precision, robustness and solution stability were well within the acceptance limit for % RSD. The proposed dissolution method for amorphous solid dispersion of Artemether is robust and discriminatory which can be explored as a tool for quality control and also for in vivo assessment.

Detecting Crystallinity in Amorphous Solid Dispersions Using Dissolution Testing: Considerations on Properties of Drug Substance, Drug Product, and Selection of Dissolution Media

Dissolution testing has long been used to monitor product quality. Its role in quality control of amorphous solid dispersion (ASD) formulations is relatively new. In the presence of the crystalline phase, the dissolution of ASDs is determined by the dynamics between the dissolution rate of the amorphous solids and the rate of crystal growth. The detection of crystalline phase by dissolution test has not been well understood in the context of drug properties, formulation characteristics and dissolution test variables. This study systematically evaluated the impact of key parameters such as intrinsic crystallization tendency of the API, drug loading, extent of dissolution sink conditions and level of crystallinity on the ASD dissolution behavior. The results indicated diverse dissolution behaviors due to the differences in the intrinsic crystallization propensity of the drug, the drug loading, the ASD polymers and the dissolution sink index. Each of the complex dissolution profiles were interpreted based on visual observations during dissolution, the appropriate sink index based on the amorphous solubility, and the competition between drug dissolution versus crystallization. The findings of this study provide insights towards the various considerations that should be taken into account towards rationally developing a discriminatory dissolution method.

Development and Validation Of A Discriminatory Dissolution Method for Portioned Moist Snuff and Snus

Portioned moist snuff and snus, two subcategories of smokeless tobacco products (STP) were dissolution tested as a quality control test. A USP Apparatus 4 was employed to develop and validate the method. The method was assessed based on time to reach nicotine dissolution plateau, percentage difference between two profiles at each time point, relative standard deviation (RSD), and f1 (similarity) and f2 (dissimilarity) values. Based on these criteria, 200 ml volume and 8 ml/min flow were found be discriminatory. The amount of nicotine dissolved from the nine products varied widely (2.0-3.4, 2.1-4.1, 3.3-4.6, 5.5-6.6, 6.9-9.1, 11.5-14.2, 12.5-14.6, 14.0-15.5, and 15.5-19.6 mg/pouch at 60 min). RSDs of the dissolution ranges were more than 20% at earlier time points and less than 20% at later timepoints. The developed method produced distinct profiles for all the tested products, which was further confirmed by f1>15 and f2<50 values. In conclusion, the developed method was discriminatory and can be employed as a quality control test and to differentiate among moist snuff and snus products.

Development and Validation of a Discriminatory Dissolution Model for an Immediately Release Dosage Form by DOE and Statistical Approaches

A discriminatory dissolution model was built through DOE with multivariate analysis of variance (MANOVA) and multiple linear regression (MLR) modeling to assess dissolution operational space for a highly water soluble immediate-release solid dosage drug product. The dissolution was utilized in the following five aspects: (1) understand the impact of individual variables and their interactions on dissolution performance through effect analysis; (2) explain the lack of discriminatory power of the initial dissolution condition used in early phase development by prediction profiler; (3) predict discriminatory dissolution operational space to differentiate photo degraded drug products from control with contour profiler analysis; (4) validate by the external experimental data acquired with the initial nondiscriminatory dissolution condition and the predicted discriminatory dissolution condition, followed by model independent statistical analysis (e.g., f2); and (5) establish correlation of the discriminatory dissolution with disintegration. The selected discriminatory dissolution method was validated by demonstrating accuracy, precision and linearity, specificity, repeatability, intermediate precision, stability, filter verification, and robustness.

Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form.

The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol® SD 200 (G1 granules) and Celphere® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD.

Development of a dissolution method for lumefantrine and artemether in immediate release fixed dose artemether/lumefantrine tablets

BackgroundDissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets.MethodsThe dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products.ResultsA suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25–100 μg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality.ConclusionsThe developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

Development and Validation of In Vitro Discriminatory Dissolution Testing Method for Fast Dispersible Tablets of BCS Class II Drug.

Fast dispersible tablets (FDTs) get dispersed very fast due to which the discrimination of in vitro drug release and their evaluation is difficult. Hence in the present study a new in vitro discriminatory dissolution method was developed and validated for FDTs of domperidone of BCS class II. FDTs of domperidone were prepared by direct compression method. The dissolution studies were performed in an eight-station Electrolab TDT-082 dissolution testing apparatus, analyzed by ultraviolet spectrophotometer and evaluated in different dissolution mediums i.e. sodium lauryl sulphate (0.5%, 1.0% and 1.5%) with fresh distilled water, simulated intestinal fluid pH 6.8, simulated gastric fluid pH 1.2 without enzymes, phosphate buffer solution (pH 6.8) and 0.1 N hydrochloric acid at different agitation speeds. The developed method was validated in terms of specificity, accuracy, precision, linearity and robustness. Amongst the different mediums, 0.5% sodium lauryl sulfate (SLS) with distilled water was found to be optimum with higher rate of discriminatory power. The percentage recovery was found to be 96 to 100.12 % and the % relative standard deviation value for precision (intraday and interday) was found to be less than 1%. Also a dissolution profile of prepared FDTs were compared in distilled water containing 0.5% SLS using similarity (f2) and dissimilarity (f1) factor calculation which showed dissimilarity in release profile and confirms the discriminatory nature of developed method. The discriminatory dissolution method for FDTs was developed and validated. All the obtained results were satisfactory, accurate and in range. The current method could be beneficial for formulation development and for assessment of quality of FDTs.

Design of Experiments Approach to Discriminatory Dissolution Method Development of Poorly Soluble Drug in Immediate Release Dosage Form

Abstract: Aim: The study involved design of experiment guided discriminatory dissolution method development for poorly soluble, ezetimibe tablets. Objective: In the current scope of study, ezetimibe tablets are selected as a suitable drug product candidate to evaluate the application of design of experiments in discriminatory dissolution method development for poorly soluble drug. Ezetimibe is practically insoluble in all the aqueous buffers. Methodology: 2-Level factorial design is selected as suitable model to build the experimental setup. Different factors like pH of dissolution media, sodium lauryl sulphate concentration, dissolution media volume and agitation speed (RPM) are selected for the study and dissolution % release at 5, 10, 15, 20, 45 min and % RSD of dissolution values at 20 min were selected as responses based on prior experience. The responses are evaluated for statistical significance and for adequacy of the built design with the help of different tools like ANOVA and diagnostic graphs. Results: It is observed that pH of dissolution media, surfactant concentration are having minimal positive effect on all of the responses. Whereas agitation speed and dissolution media volume were having significant positive effect on all responses, except for % RSD at 20 min and is inversely proportional to agitation speed. Conclusion: With the current scope of study design of experiments as an effective tool for discriminatory dissolution method development is employed to prove adequacy. Selected solutions from predictions were executed for experimental results and were compared against predictions to validate model. Key words: DoE, Discriminatory dissolution method, Ezetimibe tablets, DoE aided dissolution method development.

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion.

Non-Sink Dissolution Conditions for Predicting Product Quality and In Vivo Performance of Supersaturating Drug Delivery Systems

With recent advances in the development of supersaturating oral dosage forms for poorly water-soluble drugs, pharmaceutical scientists are increasingly applying in vitro dissolution testing under non-sink conditions for a direct evaluation of their ability to generate and maintain supersaturation as a predictive surrogate for ensuring product quality and in vivo performance. However, the scientific rationale for developing the appropriate non-sink dissolution methodologies has not been extensively debated. This calls for a comprehensive discussion of recent research efforts on theoretical and experimental considerations of amorphous solubility, liquid–liquid phase separation, and phase transitions of drugs in a supersaturated solution when dissolution testing is performed under supersaturated non-sink conditions. In addition, we outline the concept of “sink index” that quantifies the magnitude of deviations from perfect sink dissolution conditions in the sink/non-sink continuum and some considerations of non-sink dissolution testing for marketed drug products. These factors should be carefully considered in recommending an adequately discriminatory dissolution method in the performance assessment of supersaturating drug delivery systems.

Development and evaluation of film coated aceclofenac and chlorzoxazone tablet with enhanced dissolution rate

Out of many complications two major problems facing in formulation industry are poor solubility and short half-life of drugs which results into poor bioavailability after oral administration. Solid dosage forms are coated for a number of reasons, the most important of which is controlling the release profiles and bioavailability of the active ingredient. Thus the development of a significant dissolution procedure for drug products with limited water solubility has been a challenge to the pharmaceutical industry. Aceclofenac (Biopharmaceutical classification Class II drug) is a novel non-steroidal anti-inflammatory drugs (NSAIDs) having anti-inflammatory and analgesic properties, and is widely used in the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. The investigation revealed that there is no official dissolution medium available in the literature. The objective of present study is to formulate film coated tablet of Aceclofenac and Chlorzoxazone having short half-life by coating with hydroxyl propyl methyl cellulose (E5 LV). Then the formulated tablets were evaluated for its physicochemical properties and in vitro release studies. The incorporation of drugs into polymer matrices is considered a valid tool in order to optimize insufficient features of the drug molecule, like solubility, stability or toxic effects. In the present work, the incorporation of aceclofenac was performed in inert HPMC and there was no chemical interaction between the drug and polymers as concluded from the FTIR studies. In the present study, parameters such as solubility, medium pH, surfactant type, dissolution behavior of formulations, stability, and discriminatory effect of dissolution testing in different dissolution mediums were studied for the selection of a proper dissolution medium. The drug showed an enhanced release rate in the dissolution media containing pH 6.8 phosphate buffer, 900 ml with 0.5 % sodium lauryl sulphate at 75 rpm for 60 min and thus was chosen as the discriminating dissolution method for film coated aceclofenac formulation. It was found that greater than 80 % of the label amount is released over 60 min.

Discriminatory Dissolution Method Development and Validation of Etoricoxib Tablets

The availability of a discriminatory dissolution method for use in either quality control testing or product evaluation in quality by design trials is mandatory for products intended for the developed market. This study demonstrates the systematic development of a discriminatory dissolution method for etoricoxib, a BCS Class 2 drug exhibiting highly pH- dependent solubility. The pH, speed, and apparatus were simultaneously optimized and tested for method variability, reproducibility, and robustness. The discriminative power of the developed method was suitably demonstrated.

Development and Validation of a Discriminating Dissolution Method for Atorvastatin Delayed-Release Nanoparticles Using a Flow-Through Cell: A Comparative Study Using USP Apparatus 4 and 1

Atorvastatin, an HMG CoA reductase inhibitor, is widely used for the treatment of dyslipidemia and prevention of cardiovascular disease. It belongs to Class 2 of the Biopharmaceutics Classification System owing to its low solubility and high permeability. In vitro dissolution testing is an essential tool for the design of a dosage form. Appropriate selection of dissolution test conditions is essential since it will help establish an appropriate in vitro-in vivo correlation (IVIVC), which is imperative for a waiver of costly bioequivalence studies. Compounds belonging to BCS Class 2 are suitable for establishing a significant IVIVC. USP Apparatus 4 (flow-through cell) is an attractive alternative to conventional dissolution methods like Apparatus 1 and 2. The ability of the apparatus to maintain sink conditions over a longer period of time has proved useful in the development of dissolution methods for poorly soluble drugs, making the development of IVIVCs easier for such drugs. Nanoparticles of atorvastatin were formulated by an emulsion-solvent evaporation method to overcome its bioavailability problems. Development of a discriminatory dissolution method for the same was attempted using a flow-through cell (Apparatus 4) because dissolution performed using Apparatus 1 did not provide complete release of the drug within 60 min. Phosphate buffer pH 6.8 with 1.5% SLS was selected as the dissolution medium based on the results of the solubility studies. Various parameters such as flow rate and sample-loading method were optimized. The dissolution method was validated with respect to various parameters as per ICH guidelines.

Development of a Discriminating Dissolution Method for Immediate-Release Soft Gelatin Capsules Containing a BCS Class II Compound

Development of a Discriminating Dissolution Method for Immediate-Release Soft Gelatin Capsules Containing a BCS Class II Compound

Impact of Nanosizing on Solubility and Dissolution Rate of Poorly Soluble Pharmaceuticals

The quantitative determination of solubility and the initial dissolution rate enhancement of crystalline nanoparticles were critically investigated using a separation-based approach (ultracentrifugation and filtration). Four poorly soluble model compounds (griseofulvin, celecoxib, compound-X, and fenofibrate) were used in this investigation. The effect of the stabilizer concentration on the solubility of the unmilled compound was determined first to quantify its impact on the solubility and used for comparing solubility enhancement upon nanosizing. Methodologies were established for ultracentrifugation, ensuring satisfactory separation of crystalline nanoparticles. The data obtained using separation-based methodologies proved to be accurate, reproducible, and were in fair agreement with what would be predicted from the Ostwald-Freundlich equation. The dissolution studies under sink conditions were proved to be less efficient in quantifying the initial dissolution rate of crystalline nanoparticles. Nonsink dissolution experiments were able to reduce the high-dissolution velocity of nanoparticles and generated the best discriminative dissolution profile. The enhancement in initial dissolution rate was significantly less than that expected from the Noyes-Whitney equation based on surface area change. This discriminatory dissolution method can potentially be used further in the modeling of crystalline nanoparticles during drug development.

Comparison of X-ray Powder Diffraction and Solid-State Nuclear Magnetic Resonance in Estimating Crystalline Fraction of Tacrolimus in Sustained-Release Amorphous Solid Dispersion and Development of Discriminating Dissolution Method

The focus of present investigation was to explore X-ray powder diffraction (XRPD) and solid-state nuclear magnetic resonance (ssNMR) techniques for amorphous and crystalline tacrolimus quantification in the sustained-release amorphous solid dispersion (ASD), and to propose discriminating dissolution method that can detect crystalline drug. The ASD and crystalline physical mixture was mixed in various proportions to make sample matrices containing 0%-100% crystalline-amorphous tacrolimus. Partial-least-square regression and principle component regression were applied to the spectral data. Dissolution of the ASD in the US FDA recommended dissolution medium with and without surfactant was performed. R(2) > 0.99 and slope was close to one for all the models. Root-mean-square of prediction, standard error of prediction, and bias were higher in ssNMR-based models when compared with XRPD data models. Dissolution of the ASD decreased with an increase in the crystalline tacrolimus in the formulations. Furthermore, detection of crystalline tacrolimus in the ASD was progressively masked with an increase in the surfactant level in the dissolution medium. XRPD and ssNMR can be used equally to quantitate the crystalline and amorphous fraction of tacrolimus in the ASD with good accuracy; however, ssNMR data collection time is excessively long, and minimum surfactant level in the dissolution medium maximizes detection of crystalline reversion in the formulation.

Development of dissolution test method for a telmisartan/amlodipine besylate combination using synchronous derivative spectrofluorimetry

The dissolution process is considered an important in vitro tool to evaluate product quality and drug release behavior. Single dissolution methods for the analysis of combined dosage forms are preferred to simplify quality control testing. The objective of the present work was to develop and validate a single dissolution test for a telmisartan (TEL) and amlodipine besylate (AML) combined tablet dosage form. The sink conditions, stability and specificity of both drugs in different dissolution media were tested to choose a discriminatory dissolution method, which uses an USP type-II apparatus with a paddle rotating at 75 rpm, with 900 mL of simulated gastric fluid (SGF without enzymes) as the dissolution medium. This dissolution methodology provided good dissolution profiles for both TEL and AML and was able to discriminate changes in the composition and manufacturing process. To quantify both drugs simultaneously, a synchronous first derivative spectrofluorimetric method was developed and validated. Drug release was analyzed by a fluorimetric method at 458 nm and 675 nm for AML and TEL, respectively. The dissolution method was validated as per ICH guidance.

Assessing the impact of nimodipine devitrification in the ternary cosolvent system through quality by design approach

Nimodipine (NM) commercial formulation has been recalled due to drug crystallization in the product. Aim of present investigation was to systematically evaluate NM ternary cosolvents systems, characterize the crystallized drug and develop discriminating dissolution method that could detect the drug crystallization in the product. Mixture design was constructed using independent components namely water (X1), glycerin (X2) and polyethylene glycol 400 (X3, PEG-400). Nineteen formulations were developed using various level of cosolvents mixture while drug concentration was kept constant. The response selected was the drug crystallized in the formulations kept at four storage conditions 5 °C, 15 °C, 25 °C and 25 °C/60% RH for four weeks. The crystallized drug was characterized by Fourier transformed infrared (FTIR), near infrared (NIR), NIR-chemical imaging and Raman spectroscopies, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy. Dissolution of formulation and modification was tested by USP method 2 in 0.25 and 0.50% sodium lauryl sulphate (SLS) aqueous media and run at 50 and 75 rpm. X1 promoted drug crystallization at all conditions of storage and reverse was true for X3. Characterization data indicated that the crystallized drug in most of the formulations were modification II, but a few formulations contained significant proportion of the modification I. Dissolution in 0.25% (w/v) SLS at 75 rpm was more discriminating in detecting the crystallization in the product compared to dissolution in 0.5% (w/v) SLS media. In summary, cosolvents system of NM was prone to crystallization depending upon the cosolvents composition and storage conditions. A more rational approach to develop NM formulation would entail a then through understanding of the causes of crystallization and their characterization in a variety of storage conditions.