Defining the design space for freeze-dried orodispersible tablets with meloxicam

Objective: This work focused on simultaneously investigating formulation variables and freeze-drying parameters when preparing orodispersible tablets with meloxicam (Mel), by a Quality by Design (QbD) approach.

Materials and methods: Methylcellulose (MC) was selected as a matrix forming agent and mannitol (Man) as cryoprotectant, both at two concentration levels. The freezing regime was also varied between fast and shelf-ramped, to find out how it affects the final products. The tablet formulations were characterized for their disintegration time, wetting properties, mechanical properties, morphology and in vitro dissolution. Response Surface Modeling completed the statistical analysis that assessed the effects of independent variables on the responses.

Results: All the responses showed good fitting to the chosen model. The increase in MC content determined a positive effect on disintegration time, wetting time, mechanical strength and a negative effect on Mel dissolution. High levels of Man-determined brittle products with low-absorption capacity and fast Mel dissolution. The freezing rate had an important effect on the structure of tablets: fast freezing determined slightly thicker pore walls with smooth surfaces, while shelf-ramped freezing led to a multiple-layer structure with increased hardness. Still, shelf-ramped freezing yielded higher Mel release, due to physical changes of the active substance during the freeze-drying process.

Conclusion: From the generated design space, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was an efficient manner of understanding formulation and process parameters at the freeze-dried orodispersible tablets preparation.     

A quality by design approach to scale-up of high-shear wet granulation process

High-shear wet granulation is a complex process that in turn makes scale-up a challenging task. Scale-up of high-shear wet granulation process has been studied extensively in the past with various different methodologies being proposed in the literature. This review article discusses existing scale-up principles and categorizes the various approaches into two main scale-up strategies – parameter-based and attribute-based. With the advent of quality by design (QbD) principle in drug product development process, an increased emphasis toward the latter approach may be needed to ensure product robustness. In practice, a combination of both scale-up strategies is often utilized. In a QbD paradigm, there is also a need for an increased fundamental and mechanistic understanding of the process. This can be achieved either by increased experimentation that comes at higher costs, or by using modeling techniques, that are also discussed as part of this review.     

Optimization of extended-release hydrophilic matrix tablets by support vector regression

Background: In this work, support vector regression (SVR) was applied to the optimization of extended release from swellable hydrophilic pentoxifylline matrix-tablets and compared to multiple linear regression (MLR). Methods: Binary mixtures comprising ethylcellulose and sodium alginate were used as the matrix-former. The matrix-former : drug weight ratio and the percentage of sodium alginate in the matrix-former were the formulation factors (independent variables) and the percentages of drug release at four different time intervals were the responses (dependent variables). Release was determined according to United States Pharmacopeia 31 for 11 pentoxifylline matrix-tablet formulations of different independent variable levels and the corresponding results were used as tutorial data for the construction of an optimized SVR model. Six additional checkpoint matrix-tablet formulations, within the experimental domain, were used to validate the external predictability of SVR and MLR models. Results: It was found that the constructed SVR model fitted better to the release data than the MLR model (higher coefficients of determination, R^?2, lower prediction error sum of squares, narrower range of residuals, and lower mean relative error), outlining its advantages in handling complex nonlinear problems. Superimposed contour plots derived by using the SVR model and describing the effects of polymer and sodium alginate content on pentoxifylline release showed that formulation of optimal release profiles, according to United States Pharmacopeia limitations, could be located at drug : matrix ratio of 1 and sodium alginate content 25% w/w in the matrix-former. Conclusion: The results indicate the high potential for SVR in formulation development and Quality by Design.     

Quality by design approach for development of suspension nasal spray products: a case study on budesonide nasal suspension

The objective of this study was to provide quality by design (QbD) approach for development of suspension type nasal spray products. Quality target product profile (QTPP) of test product budesonide nasal suspension (B-NS) was defined and critical quality attributes (CQAs) were identified. Critical formulation, process and delivery device variables were recognized. Risk assessment was performed by using failure mode and effect analysis (FMEA) methodology. Selected variables were further assessed using a Plackett Burman screening study. A response surface design consisting of the critical factors was used to study the interactions between the study variables. Formulation variable X₂: median particle size of budesonide (D₅₀) (µ) has strikingly influenced dissolution (%) (Y₁), while D₅₀ droplet size distribution (µm) (Y₂) was significantly impacted by formulation variable X₁: Avicel RC 591 (%) and process variable X₄: homogenization speed (rpm). A design space plot within which the CQAs remained unchanged was established at lab scale. A comprehensive approach for development of B-NS product based on the QbD methodology has been demonstrated. The accuracy and robustness of the model were confirmed by comparability of the predicted value generated by model with the observed value.     

基于保质设计方法的产品开发决策研究

讨论了保质设计思想指导下的产品开发设计策略,并以产品开发设计的关键阶段——概念设计为对象,进一步研究了产品概念设计决策过程,建立了产品概念设计方案的评价指标体系和基于模糊优选理论的决策模型.     

Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept

Context: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability.

Objective: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation.

Materials and methods: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug.

Results and discussion: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed T_max, improved C_max and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption.

Conclusion: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.     

Formulation study of a patch containing propranolol by design of experiments

Objective: To evaluate the feasibility of a transdermal patch containing propranolol (PR).

Method: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2⁴ full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test.

Results: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X₁, p?=?0.0957) and PR content (X₃, p?=?0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X₄, p?=?0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7?μg/cm²/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100–120 cm², since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs.

Conclusion: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3?μg/cm²/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50?μm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48?h.     

Layer by layer deposition of hydroxyapatite onto the collagen matrix

Layer by layer (LbL) deposition is a useful method for deposition of many inorganic (including metals, oxides and phosphates) and organic (including polymers and proteins) components on a large range of substrates. The LbL deposition of hydroxyapatite (HA) onto a collagen matrix involves HA synthesis on the collagen matrix starting from electrically charged precursors such as Ca²⁺ and PO₄³⁻ at a proper pH to precipitate the desired calcium phosphate.The LbL deposition process was continuously monitored in order to study the amount of HA deposited in each layer. The deposition of the first layers of HA was concluded to be highly influenced by the collagen matrix. When the collagen matrix is crosslinked with glutaraldehyde, the matrix structure is not modified during the deposition, and the porosity will decrease with the number of layers until saturation is reached. Following pore saturation, HA will be only deposited onto the mineralized collagen matrix surface. The obtained composite materials were characterized by XRD, SEM, DTA-TG and FTIR.     

Modular design of product families for quality and cost

The purpose of this article is to help managers early in the design of new product families. Based on product structures, sales forecasts, and constraints imposed by the marketplace, like quality and cost, the proposed method selects the product modules that meet customer requirements for the products, while respecting those constraints. The proposal includes a single-level module design formulation that considers quality and cost simultaneously. The method for testing the proposed algorithm is based on a case study of an electro–mechanical assembly device (headlamp). The performance of the algorithm is compared to that of the zero module case, where often the constraint problem cannot be resolved. The main result is a model and an algorithm that optimise quality and cost under the constraints of quality and cost. It shows what modules to manufacture, in what quantities, and in which products to use them. The output also provides the predicted quality and cost, based on improvements made to the modules. To conclude, this research enables the joint optimisation of quality and cost by defining the modules to be manufactured. It provides input for managers seeking modules designed for their supply chain. The algorithm provides key input for managing production ramp-up.     

Cubosomal based oral tablet for controlled drug delivery of telmisartan: formulation,in-vitro evaluation and in-vivo comparative pharmacokinetic study in rabbits

A nanoparticulate system; cubosomes has been suggested to support the controlled release of Telmisartan (TEL), a poorly water-soluble medication. Four distinctive formulae were selected according to the results of three estimated responses. The liquid cubosomes were successfully adsorbed onto Aerosil 380 to form granules. The formulae were evaluated for their flow properties. The best granules were compressed into tablets suitable for oral administration. The tablets were evaluated for its performance. The in vivo study of the best selected cubosomal tablets was checked after oral administration in the blood of albino rabbits utilizing an HPLC method. Results revealed that the highest EE was shown in formulae C5 (59.68?±?1.3). All the prepared formulae had particle size less than 500?nm with PDI < 0.5 and the highest zeta potential results were observed in C5, C7, C9, C11 and C12 (>30?mv). A7 and A9 prepared using Aerosil 380 showed a perfect flowability. After 1?h of dissolution testing, the commercial product showed a 66% drug release while the release of all cubosomal formulae didn’t exceed 35% during the first hour reaching a 85% of the drug released at the end of 24?h. A7 was selected for the in vivo study; T_max of TEL absorption is increased for cubosomal formula by three folds indicating sustained release pattern. The relative bioavailability is also increased by 2.6 fold. The investigation proposed the rationality of cubosome to figure an effective controlled release tablets to improve its bioavailability and expand its activity.     

Development of sustained release gastro-retentive tablet formulation of nicardipine hydrochloride using quality by design (QbD) approach

The objective of the present study was to develop a sustained release gastro-retentive (SRGR) tablet formulation of nicardipine hydrochloride (HCl) for once-a-day dosing using the quality by design (QbD) approach. The quality target product profile of nicardipine HCl SRGR tablet formulation was defined, and critical quality attributes (CQAs) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tool and screened by the Plackett–Burman design, and finally nicardipine HCl SRGR tablet formulation was optimized using the Box–Behnken design. The tablets were prepared by a direct compression technique using polymers such as hydroxypropylmethylcellulose (HPMC K15M), glyceryl behenate, alone or in combinations and other standard excipients. Sodium bicarbonate was incorporated as a gas-generating agent. The effects of polymers and sodium bicarbonate on the drug release profile and floating properties were investigated as these parameters are likely to affect the desired once-a-day dosing regimen and finally the therapeutic efficacy of SRGR drug delivery systems. It was observed that formulation variables X₁: Glyceryl behenate (mg/tab) and X₂: HPMC K15M (mg/tab) strikingly influenced the drug release (%) (Y₁), whereas floating lag time (min) (Y₂) was significantly impacted by the formulation variable X₃: Sodium bicarbonate (mg/tab). A design space plot within which the CQAs remained unchanged was established at a lab scale. In conclusion, this study demonstrated the suitability of a glyceryl behenate-HPMC K15M polymer combination along with sodium bicarbonate to achieve SRGR tablet formulation for once-a-day dosing of nicardipine HCl using the systematic QbD approach.     

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex®-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol® 888ATO, Eudragit® RS, Methocel® K100M, Polyox® WSR301 and Precirol® ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol® and hydrophilic Methocel® produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.     

Sequential optimization of parameter and tolerance design for multiple dynamic quality characteristics

System design, parameter design and tolerance design are the three stages of design process as presented by G. Taguchi. Systems design identifies the basic elements of the design to provide new or improved products to customers. Parameter design determines the optimal parameter settings, which will minimize variation from the target performance of the product. Tolerance design finally identifies the components of the design, which are sensitive in terms of affecting the quality of the product, and establishes tolerance limits that will give the required level of variation in the design. Most studies have focused primarily on optimizing the parameter design or tolerance design for multiple static quality characteristics. In this paper, a mathematical formula corresponding to the model is derived from Taguchi's quadratic quality loss function to minimize the expected total cost for the parameter design of multiple dynamic quality characteristics. When the optimal parameter design is not sufficient to reduce the output variation, the first-order Taylor series expansion is then used to analyse the variations of noise factors for optimizing the tolerance design. It concludes with an example demonstrating this approach.     

Power of experimental design studies for the validation of pharmaceutical processes: case study of a multilayer tablet manufacturing process

Experimental design studies (EDS) are already widely used in the pharmaceutical industry for drug formulation or process optimization. Rare are the situations in which this methodology is applied for validation purposes. The power of this statistical tool, key element of a global validation strategy, is demonstrated for a multilayer tablet manufacturing process. Applied to the Geomatrix® system generally composed of one compression and three granulation processes, time and strictness gains are non-negligible. Experimental design studies are not used in this work for modeling. Introduced at each important step of the process development, they allow for the evaluation of process ruggedness at pilot scale and specifications for full production. A demonstration of the complete control of key process parameters is given, identified throughout preliminary studies.     

A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables,wet media milling process parameters and excipient variability on drug product quality attributes

Abstract

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon^® VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.     

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, S_mix, and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100?±?0.1% transmittance and 17.85?±?2.78?nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value ?5.88?±?1.14?mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.     

基于Matrix 2003与效应的产品工业设计创新方法研究

产品创新直接关系到产品自身在市场的竞争力.当前工业设计产品创新缺乏一些具体的理论支撑,因此需要将其他领域的理论融入工业设计当中能够有效提高新产品设计的效率.为提高工业设计中的创新效率,介绍了一种将工业设计理论与Matrix 2003结合的创新原理,总结了六大设计要素,并利用这些设计元素将创新原理按照"时间-空间-交互"三大维度进行划分,形成一种独特的创新矩阵,以最终理想产品所达到的效应为目标进行求解,从而为工业设计产品的创新提供了一种快捷有效的方法流程.最后以快递车车厢的改进为工程实例进一步验证方法的有效性和实用性.     

Role of continuous moisture profile monitoring by inline NIR spectroscopy during fluid bed granulation of an Enalapril formulation

Background: Granulation and tableting are closely related process steps in the supply chain of pharmaceutical products. Even today, these steps are still optimized independently by trial and error. On the framework of a process analytical technology approach, these processes were evaluated in an integrated approach. Enalapril maleate is a low-dose drug substance with poor granulating and tableting behavior. In order to verify how granulation influences tableting properties, different granulation experiments were performed. Methods: Granulation experiments with fast spraying rate and fast drying as well as fast spraying rate and slow drying, and also combinations of both were run. The obtained granules were then promptly compressed into tablets in a rotary press and subjected to hardness testing. The progress of spraying and drying was controlled by a continuous near-infrared spectroscopic measuring setup. This study confirms that the tablet characteristics. Result/Conclusion: after compression of the granules in comparison to placebo granules are dependent not only on the residual moisture content of the granules but also on the moisture profiles during the entire fluid bed granulation process.