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The present study demonstrated the prediction of predominant root causes of capping behavior as a function of the powder rheological and the mechanical behavior of Acetaminophen ...(APAP) and Ibuprofen (IBU). The authors analyzed powder rheological properties for powder blend permeability, pressure drop, and cohesion. The measured deformation properties were compact porosity, internal air pressure, Brinell hardness, and tensile strength. The data were evaluated qualitatively and quantitatively using multivariate techniques, such as principal component analysis (PCA) and principal component regression (PCR) models, respectively, to identify the effect of powder air entrapment efficiency and mechanical behavior on the tablet capping score. The PCA model indicated that pressure drop, cohesion, API amount, and compression pressure correlated positively, whereas permeability, porosity, internal air pressure, Brinell hardness, and tensile strength correlated negatively to the capping potential. APAP and IBU also showed two independent mechanisms as a function of their amount on the capping score at all compression pressures. APAP and IBU followed an exponential and linear relationship, respectively. Furthermore, the dominant powder rheological and deformation behavior affecting the capping score of each material was identified and quantified using two separate PCR models. These models showed that APAP capping was predominantly dependent on its powder properties, while that of IBU was predominantly based on its deformation properties. In conclusion, APAP and IBU compacts capping had respective air induced and deformation induced capping behavior. The proposed approach can aid in understanding the underlying mechanisms of capping and developing an effective, optimized strategy to ensure tablet quality.
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•Pycnometric tablet density can resolve Heckel negative porosity issue.•New approach allows efficient use of full Heckel plot without negative porosity.•New approach can overcome the ...limitations of modified Heckel equation approach.
A parameterization of compaction simulator generated dynamic compression profile with a few grams of powder provides important information about the material deformation and compact elasticity. The Heckel equation is by far the most popular choice among pharmaceutical scientists for such parametrization. A general approach of Heckel analysis uses pycnometric powder density (ρP0) for relative density calculation. However, as ‘in-die’ tablet bulk density at applied compression pressure (ρBP) becomes greater than or equal to the measured ρP0, the general approach typically poses a negative porosity challenge at high compression pressure regions. It is only theoretically possible to have a tablet with zero or negative porosity. Negative porosity may be detected during ‘in-die’ compression analysis, but it will not exist after ejection of the tablet in practical aspect. Thus, the present work proposes a new approach to using pycnometric tablet density (ρPP) in the relative density calculations of Heckel analysis. This ρPP may be a better representation of actual tablet particle volume, as it is composed of non-accessible intra-particulate pores, which are broken under applied compression pressure. A new approach showed its immunity for Heckel high-pressure negative porosity. It enables the utilization of the compression and decompression phases of dynamic compression profiles to evaluate macroscopic compaction performance. The proposed approach was validated with a reported modified Heckel approach. The Heckel parameters computed with both methodologies for microcrystalline cellulose and lactose were not statistically different. However, a modified Heckel approach was unable to compute Heckel parameters of poorly compacting starch unlike the new approach. A modified Heckel approach became invalid during starch compaction at low compression pressures (below 400 MPa), where starch was forming weaker but still intact tablets. Certainly, a complete Heckel profiling with a new approach could save time and costs in an early development stage for designing and screening scientifically based lead prototype formulations.
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A QbD-DM3 linked rational product design strategy was adopted to create a hybridized ritonavir (RTV, BCS Class IV) nanoamorphous micellar dispersion (RTV-NAD). A DM3 research strategy ...was employed in conjunction with the quality-by-design spaces, and quality target product profile to link the critical material attributes and critical process parameters to the quality target product profile’s critical product attributes QbD elements. A Box-Behnken design and multivariate analysis using multiple linear regression and partial least squares provided data analysis. The hybridized strategy leveraged three different mechanisms to increase RTV's solubility and four mechanisms to increase its dissolution rate. Statistically significant models were generated for critical product attributes: particle size (p = 0.0000, R2 adjusted = 0.9513), polydispersity index (p = 0.0002, R2 adjusted = 0.6398), zeta potential (p = 0.0000, R2 adjusted = 0.9744), and drug loading on a dry basis (p = 0.0000, R2 adjusted = 0.9951). The impact of drug concentration, Soluplus® concentration, and solvent:antisolvent ratio, their interactions and square effects on the critical product attributes were assessed by multivariate analysis.
The QbD optimal formulation was determined for RTV-NAD. Multiple linear regression and partial least squares computational predictability was evaluated using three verification batches. The prediction error for critical product attributes was <5%.
RTV-NAD and ritonavir microsuspension were characterized by x-ray diffraction and in-vitro dissolution studies. X-ray diffraction confirmed the amorphous nature of the RTV-NAD. RTV-NAD exhibited a ‘spring-hover’ dissolution profile at pH 4.5. At pH 6.8, a classic ‘spring-parachute’ dissolution behavior was observed.
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Drug-drug cocrystals (DDC) represent a unique subset of pharmaceutical materials offering distinct advantages in combination therapies, pharmacokinetics, and patient compliance. ...However, their structure–function relationships are rarely reported despite its central importance in successful medicine. A material-sparing approach consisting of a molecular and structural perspective is reported to evaluate tabletability of a model DDC, metformin:salicylic acid, relative to its components: metformin HCl (MET) and sodium salicylate (SAL). MET alone displayed a very poor tabletability, which could be attributed to its isotropic and stiff interaction topology. SAL displayed a highly anisotropic interaction topology with layers of strongly hydrogen-bonded salicylate molecules promoting deformation and tabletability. This is also confirmed by its low moduli. DDC yielded intermediate stiffness and elastic anisotropy material with an improved plastic flow and overall better tabletability. Overall, DDC is a promising therapeutic class requiring the physical–mechanical evaluation to assure their processability to enjoy their therapeutic advantages.
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A QbD-DM3 strategy was used to design ketoprofen (KTF) optimized liquid (L-SNEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS). Principal component analysis was ...used to identify the optimized L-SNEDDS containing Capmul® MCM NF, 10 % w/w; Kolliphor® ELP, 60 % w/w; and propylene glycol, 30 % w/w. The S-SNEDDS was manufactured by spray-drying a feed dispersion prepared by dissolving the optimized KTF-loaded L-SNEDDS in an ethanol-Aerosil® 200 dispersion. A Box Behnken design was employed to evaluate the effect of drug concentration (DC), Aerosil® 200 concentration (AC) and feed rate (FR) on maximizing percent yield (PY) and loading efficiency (LE). The optimal levels of DC, AC, and FR were 19.9 % w/w, 30.0 % w/w, and 15.0 %, respectively. The optimized S-SNEDDS was amorphous, and its dissolution showed a 2.37-fold increase in drug release compared to KTF in 0.1 HCl. An optimized independent spray-dried S-SNEDDS verification batch showed that the predicted and observed PY and LE were 70.49 % and 92.49 %, and 70.02 % and 91.27 %, respectively. The optimized L-SNEDDS and S-SNEDDS also met their quality target product profile criteria for globule size <100 nm, polydispersity index < 0.400, emulsification time < 30 s, and KTF L-SNEDDS solubility 100-fold greater than its water solubility.
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For the first time, isoniazid (INH) bitterness value, threshold, and sensitivity (low, moderate, high, and extremely high) was determined in six human volunteers. INH demonstrated a ...large range in bitterness sensitivity. The current work demonstrates the design of a taste-masked isoniazid (INH)-loaded chitosan microspheres (INH-LCM) using an ionic-gelation and spray drying technique. A 24 full factorial design with three center points was employed to optimize and study the independent variables (chitosan concentration, sodium tripolyphosphate (TPP)-volume, feed rate, and air inlet temperature) effects on the critical quality attributes (percent yield PY and entrapment efficiency EE). Statistically significant models were developed for PY (p = 0.0357; adjusted R2 = 0.6078) and EE (p = 0.0190; adjusted R2 = 0.6713). A multicriteria prediction profiler was utilized to determine the optimum formulation and process parameters. Two verification batches confirmed excellent predictability and lot-to-lot consistency. In vitro dissolution was used to evaluate the taste masking ability of INH-LCM. The in vitro dissolution test of the optimized INH-LCM suggested that taste masking would be accomplished for the “low” and “moderate” bitterness taste sensitivity groups. Further in vitro and human volunteer taste panel studies with INH-LCM are required for better understand the potential taste masking capability for the “high” and “extremely high” bitterness taste sensitivity groups. The in vitro dissolution method and FTIR data analysis support that TPP crosslinked chitosan may provide taste masking by two mechanisms: (1) acts as a physical barrier and delays INH dissolution; and (2) provides a chemical barrier by forming hydrogen bonds between INH's bitter tasting amino group and chitosan.
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Magnesium stearate (MgSt) is the most commonly used excipient for oral solid dosage forms, yet there is significant commercial physicochemical variability that can lead to variable ...performance of critical product attributes. Differential scanning calorimetry (DSC) is often used as a quality control tool to characterize MgSt, but little data is available regarding the physicochemical relevance for the DSC thermograms. The main aim of this study was to decipher MgSt’s complex thermotropic behavior using DSC, thermogravimetric analysis, capillary melting point, polarized hot-stage microscopy, and temperature dependent small-angle X-ray scattering (SAXS) and assign physicochemical relevance to the DSC thermograms. Several DSC thermal transitions are irreversible after the first heating cycle of a heat-cool-heat-cool-heat cycle. Interestingly, after the first heat cycle, the complex cool-heat-cool-heat DSC thermograms were highly reproducible and exhibited 6 reversible exothermic-endothermic conjugate pairs. SAXS identified 5 distinct mesophases at different temperatures with Phase C′ persisting to 250 °C. MgSt maintained molecular ordering beyond 276 °C and did not undergo a simple melting phenomena reported elsewhere. This research serves as a starting point to design heat-treatment strategies to create more uniform MgSt starting material.
Purpose
Increased tablet anisotropy could lead to increased tablet capping propensity. Tooling design variables such as cup depth could serve as a key player for inducing tablet anisotropy.
Methods
A ...new capping index (CI) consisting of the ratio of compact anisotropic index (CAI) and material anisotropic index (MAI) is proposed to evaluate tablet capping propensity as a function of punch cup depth. CAI is the ratio of axial to radial breaking force. MAI is the ratio of axial to radial Young’s modulus. The impact of various punch cup depths flat face, flat face beveled edge, flat face radius edge, standard concave, shallow concave, compound concave, deep concave, and extra deep concave on the capping propensity of model acetaminophen tablets was studied. Tablets were manufactured at 50, 100, 200, 250, and 300 MPa compression pressure at 20 RPM on different cup depth tools using Natoli NP-RD30 tablet press. A partial least squares model (PLS) was computed to model the impact of the cup depth and compression parameters on the CI.
Results
The PLS model exhibited a positive correlation of increased cup depth to the capping index. The finite elemental analysis confirmed that a high capping tendency with increased cup depth is a direct result of non-uniform stress distribution across powder bed.
Conclusions
Certainly, a proposed new capping index with multivariate statistical analysis gives guidance in selecting tool design and compression parameters for robust tablets.
The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite ...experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.
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