Modulation of the wettability of excipients by surfactant and its impacts on the disintegration and release of tablets

Objective: To investigate the modulation of the wettability of excipients by different types of surfactants and its impacts on the disintegration of tablets and drug release.

Materials and methods: The critical micelle concentration (CMC) of surfactants, including sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS), dodecyl trimethyl ammonium bromide (DTAB), cetyltrimethyl ammonium bromide (CTAB) and polysorbate (Tween-20 and Tween-80), was obtained using the platinum ring method. Contact angles of surfactant solutions on the excipient compacts and double-distilled water on the mixture of surfactant and the other excipient (magnesium stearate (MgSt) or sodium alginate (SA)) were measured by the sessile drop technique. Besides, surface free energy of excipients was calculated by the Owens method. Finally, the disintegration of tablets and in vitro dissolution testing were performed according to the method described in USP.

Results and discussion: The wettability of excipients could be enhanced to different extent with low concentration of surfactant solutions and maintained stable basically after CMC. For MgSt (hydrophobic excipient), the shorter the hydrophobic chain (C₁₂, including SDS and DTAB), the better the wettability with the addition of surfactant in the formulation, leading to the shorter disintegration time of tablets and higher drug release rate. In contrast, the wettability of SA (hydrophilic excipient) was reduced by adding surfactant, resulting in the longer disintegration time of tablets and lower release rate.

Conclusion: The modulation of the wetting of pharmaceutical excipients by surfactant had changed the disintegration time of tablets and drug release rate to a greater extent.     

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press

Context: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected.

Objective: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS).

Materials and methods: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder.

Results and discussion: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures.

Conclusion: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.     

Development of optimized self-nanoemulsifying lyophilized tablets (SNELTs) to improve finasteride clinical pharmacokinetic behavior

Objective: Preparation of an optimized finasteride (FSD) lyophilized tablets loaded with self-nanoemulsifying drug delivery system (SNEDDS).

Significance: Enhance FSD bioavailability in male pattern baldness and benign prostatic hyperplasia.

Methods: Two-step optimization was implemented to achieve the study goals. First; the mixture design was used to develop an optimized SNEDDS through which the effect of cosurfactant number of carbon atoms on SNEDDS particle size and thermodynamic stability has been tested. Second; the different tablet excipients have been used to develop an optimized self-nanoemulsifying lyophilized tablets (SNELTs). The prepared tablets have been fully characterized. Interaction among tablet components has been studied. Finally, FSD clinical pharmacokinetic has been investigated on human volunteers.

Results: Anise oil and tween 80 were selected as oily phase and surfactant, respectively while different aliphatic alcohols were studied as cosurfactants. Percentages of oil, surfactant, and cosurfactants were significantly affecting SNEDDS particle size. Increasing cosurfactant number of carbon atoms achieved smaller particle size and higher stability. The optimized SNEDDS was found to contain 10.3455, 45.8972, and 43.7573% of anise oil, tween 80, and butanol, respectively. Variations in FSD cumulative release and disintegration time, from the prepared tablets, were attributed to change in the percent of plasdone XL, Avicel and silica. No interaction among components was noticed. Clinical pharmacokinetics illustrated significant enhancement in the studied parameters from the optimized lyophilized tablets loaded with drug SNEDDS when compared to marketed FSD product.

Conclusion: Lyophilized tablets could be considered as a good alternative for conventional solid dosage forms especially when loaded with drug nanosystems.     

Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system

Context: Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach.

Objective: Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material.

Materials and methods: Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM.

Results: LSH tablets exhibited dynamic swelling–deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (<10%) at pH 1.2 and higher release at pH 6.8 and 7.4. SEM showed elongated channels in swollen then freeze-dried tablets.

Discussion: The drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion.

Conclusions: These finding indicates that LSH holds potential to be developed as sustained release material for tablet.     

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.     

Controlled precipitation for enhanced dissolution rate of flurbiprofen: development of rapidly disintegrating tablets

Objective: The aim of this work was to investigate the potential of controlled precipitation of flurbiprofen on solid surface, in the presence or absence of hydrophilic polymers, as a tool for enhanced dissolution rate of the drug. The work was extended to develop rapidly disintegrated tablets.

Significance: This strategy provides simple technique for dissolution enhancement of slowly dissolving drugs with high scaling up potential.

Methods: Aerosil was dispersed in ethanolic solution of flurbiprofen in the presence and absence of hydrophilic polymers. Acidified water was added as antisolvent to produce controlled precipitation. The resultant particles were centrifuged and dried at ambient temperature before monitoring the dissolution pattern. The particles were also subjected to FTIR spectroscopic, X-ray diffraction and thermal analyses.

Results: The FTIR spectroscopy excluded any interaction between flurbiprofen and excipients. The thermal analysis reflected possible change in the crystalline structure and or crystal size of the drug after controlled precipitation in the presence of hydrophilic polymers. This was further confirmed by X-ray diffraction. The modulation in the crystalline structure and size was associated with a significant enhancement in the dissolution rate of flurbiprofen. Optimum formulations were successfully formulated as rapidly disintegrating tablet with subsequent fast dissolution.

Conclusions: Precipitation on a large solid surface area is a promising strategy for enhanced dissolution rate with the presence of hydrophilic polymers during precipitation process improving the efficiency.     

Evaluation of non-crystalline cellulose as a novel excipient in solid dose products

Objective: The objective of this study was to evaluate non-crystalline cellulose (NCC) as a novel tablet excipient in solid oral dosage forms in comparison with microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (Prosolv®, SMCC).

Significance: MCC, although a widely used tablet excipient, has diasdvantages in terms of its low dilution potential for potent drugs, and sensitivity to lubricant and moisture. SMCC, a modified version of MCC, has improved tablet compression properties. However, SMCC is expensive and also affects the moisture sorption and particle deformation during compression leading to increased tensile strength and tablet hardness. NCC was found to be similar to SMCC in its performance as a tablet excipient and thus can serve as a cheaper alternative to SMCC.

Methods: Scanning electron microscopy (SEM), X-ray diffrectometry (XRD), and differential scanning calorimetry (DSC) analyses were performed on NCC, MCC, and SMCC. Further, out-of-the die Heckel, Kawakita compact densification and stress-strain analyses were performed to evaluate their compaction and compressibility properties. Various compendial and non-compendial tests were performed to to determine the flow properties of materials. Dissolution studies were performed using amlodipine besylate as a marker drug.

Results: It was found that NCC has similar or even better flow properties and compactibility than MCC due to its porous and amorphous structure whereas it had similar properties as SMCC.

Conclusions: Based on the data, it can be concluded that NCC can serve as a cheaper and better alternative to MCC as excipient in solid dosage forms.     

Physical barrier type abuse-deterrent formulations: monitoring sintering-induced microstructural changes in polyethylene oxide placebo tablets by near infrared spectroscopy (NIRS)

Objective: The monitoring and evaluation of sintering-induced tablet strength of a polyethylene oxide (PEO) based placebo tables was accomplished using infrared spectroscopy (NIRS).

Significance: Evaluation of high molecular weight PEO-based tablet matrices for abuse deterrent formulation applications is an analytical challenge. NIRS is one tool that can provide physical and chemical evaluation of this polymer and tablet system. In addition, the use of NIRS as a process analytical tool (PAT) to monitor oven sintering of pharmaceutical tablets has not been recorded in the literature. The multiplicative scattering correction (MSC) algorithm was also successfully applied as a new and fast way to calculate NIRS spectral slopes and intercepts to build models against tablet tensile strength with respect to sinter time.

Methods: Both spectral slope regression (SSR) and spectral intercept regression (SIR) models were compared to commonly used partial least squares analysis (PLS) to evaluate placebo PEO based pharmaceutical tablets comprised of PEO at 70, 50, 30% w/w that were compressed at two solid fraction (SF) levels.

Results: All three regression techniques, PLS, SSR, SIR, were evaluated for robustness and reliability and physical relevancy to the system studied. The methods were ranked in utility with SSR being the best method followed by SIR then PLS.

Conclusions: The MSC algorithm was presented to quickly calculate spectral slopes and intercepts for use in SSR and SIR analysis. SSR models were successfully applied and assessed as the optimal modeling technique to monitor sintering of PEO-based matrix tablets.     

A novel method for determination of the filling level in the feed frame of a rotary tablet press

Aim: The aim of this study was to investigate whether the filling level within the feed frame of a rotary tablet press can be quantified by laser triangulation combined with the angle recognition of one paddle wheel via rotary encoder.

Significance: Rotary tablet press feed frames are supposed to assure a uniform die filling and, thus, to guarantee the weight and content uniformity of the resulting tablets. Therefore, a constant bulk availability and flow within the feed frame is crucial and has to be ensured by the feed frame design and the operating conditions. So far, there is no instrument available to monitor the bulk filling level or the bulk distribution within feed frames.

Methods: Calcium phosphate dihydrate was used as model powder. The powder surface level was determined via laser triangulation and the angle position of the paddle wheel was monitored via incremental rotary encoder. The data of both parameters was acquired synchronously and evaluated by in-house written software.

Results: Different powder masses led to significantly different filling level signals. The experiments showed a high reproducibility of the determined filling levels. Furthermore, an influence of the rotational speed on the powder distribution was observed.

Conclusions: The developed instrument may be used for quantification of the volumetric filling level within rotary tablet press feed frames. It may either be used to better understand the powder behavior within feed frames or for improvement of the die filling process by implementing the device into a feedback loop.     

Reduction of tablet weight variability by optimizing paddle speed in the forced feeder of a high-speed rotary tablet press

Context: Tableting is a complex process due to the large number of process parameters that can be varied. Knowledge and understanding of the influence of these parameters on the final product quality is of great importance for the industry, allowing economic efficiency and parametric release.

Objective: The aim of this study was to investigate the influence of paddle speeds and fill depth at different tableting speeds on the weight and weight variability of tablets.

Materials and methods: Two excipients possessing different flow behavior, microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate (DCP), were selected as model powders. Tablets were manufactured via a high-speed rotary tablet press using design of experiments (DoE). During each experiment also the volume of powder in the forced feeder was measured.

Results and discussion: Analysis of the DoE revealed that paddle speeds are of minor importance for tablet weight but significantly affect volume of powder inside the feeder in case of powders with excellent flowability (DCP). The opposite effect of paddle speed was observed for fairly flowing powders (MCC). Tableting speed played a role in weight and weight variability, whereas changing fill depth exclusively influenced tablet weight.

Conclusion: The DoE approach allowed predicting the optimum combination of process parameters leading to minimum tablet weight variability. Monte Carlo simulations allowed assessing the probability to exceed the acceptable response limits if factor settings were varied around their optimum. This multi-dimensional combination and interaction of input variables leading to response criteria with acceptable probability reflected the design space.     

Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations

Objective: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching.

Methods: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors – roller compaction pressure, intragranular filler percent and filler type – were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors.

Results: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index.

Conclusion: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.     

Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary absorption of encapsulated insulin compared with co-administered insulin

Objective: We have previously shown that aerosolized liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhance the pulmonary absorption of encapsulated insulin. In this study, we aimed to compare insulin encapsulated into the liposomes versus co-administration of empty liposomes and unencapsulated free insulin, where the DPCC liposomes would serve as absorption enhancer.

Significance: The present study provides the useful information for development of noninvasive treatment of diabetes.

Methods: Co-administration of empty DPPC liposomes and unencapsulated free insulin was investigated in vivo to assess the potential enhancement in protein pulmonary absorption. Co-administration was compared to DPPC liposomes encapsulating insulin, and free insulin.

Results: DPPC liposomes enhanced the pulmonary absorption of unencapsulated free insulin; however, the enhancing effect was lower than that of the DPPC liposomes encapsulating insulin. The mechanism of the pulmonary absorption of unencapsulated free insulin by DPPC liposomes involved the opening of epithelial cell space in alveolar mucosa, and not mucosal cell damage, similar to that of the DPPC liposomes encapsulating insulin. In an in vitro stability test, insulin in the alveolar mucus layer that covers epithelial cells was stable. These findings suggest that, although unencapsulated free insulin spreads throughout the alveolar mucus layer, the concentration of insulin released near the absorption surface is increased by the encapsulation of insulin into DPPC liposomes and the absorption efficiency is also increased.

Conclusion: We revealed that the encapsulation of insulin into DPPC liposomes is more effective for pulmonary insulin absorption than co-administration of DPPC liposomes and unencapsulated free insulin.     

Integrating biopharmaceutics risk assessment and in vivo absorption model in formulation development of BCS class I drug using the QbD approach

Objective: Clinically relevant critical quality attributes (CQA’s) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored.

Significance: A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development.

Methods: Factorial design of experiments was employed to study the effect of formulation and process variables on CQA’s. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption.

Results: BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the active pharmaceutical ingredient (API) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time and filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity.

Conclusions: Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.     

Applying the approximation method PAINT and the interactive method NIMBUS to the multiobjective optimization of operating a wastewater treatment plant

Using an interactive multiobjective optimization method called NIMBUS and an approximation method called PAINT, preferable solutions to a five-objective problem of operating a wastewater treatment plant are found. The decision maker giving preference information is an expert in wastewater treatment plant design at the engineering company Pöyry Finland Ltd. The wastewater treatment problem is computationally expensive and requires running a simulator to evaluate the values of the objective functions. This often leads to problems with interactive methods as the decision maker may get frustrated while waiting for new solutions to be computed. Thus, a newly developed PAINT method is used to speed up the iterations of the NIMBUS method. The PAINT method interpolates between a given set of Pareto optimal outcomes and constructs a computationally inexpensive mixed integer linear surrogate problem for the original wastewater treatment problem. With the mixed integer surrogate problem, the time required from the decision maker is comparatively short. In addition, a new IND-NIMBUS^® PAINT module is developed to allow the smooth interoperability of the NIMBUS method and the PAINT method.     

High throughput research and evaporation rate modeling for solvent screening for ethylcellulose barrier membranes in pharmaceutical applications

Context: Ethylcellulose is commonly dissolved in a solvent or formed into an aqueous dispersion and sprayed onto various dosage forms to form a barrier membrane to provide controlled release in pharmaceutical formulations. Due to the variety of solvents utilized in the pharmaceutical industry and the importance solvent can play on film formation and film strength it is critical to understand how solvent can influence these parameters.

Objective: To systematically study a variety of solvent blends and how these solvent blends influence ethylcellulose film formation, physical and mechanical film properties and solution properties such as clarity and viscosity.

Materials and methods: Using high throughput capabilities and evaporation rate modeling, thirty-one different solvent blends composed of ethanol, isopropanol, acetone, methanol, and/or water were formulated, analyzed for viscosity and clarity, and narrowed down to four solvent blends. Brookfield viscosity, film casting, mechanical film testing and water permeation were also completed.

Results and discussion: High throughput analysis identified isopropanol/water, ethanol, ethanol/water and methanol/acetone/water as solvent blends with unique clarity and viscosity values. Evaporation rate modeling further rank ordered these candidates from excellent to poor interaction with ethylcellulose. Isopropanol/water was identified as the most suitable solvent blend for ethylcellulose due to azeotrope formation during evaporation, which resulted in a solvent-rich phase allowing the ethylcellulose polymer chains to remain maximally extended during film formation. Consequently, the highest clarity and most ductile films were formed.

Conclusion: Employing high throughput capabilities paired with evaporation rate modeling allowed strong predictions between solvent interaction with ethylcellulose and mechanical film properties.     

A study of photostability and compatibility of the anti-chagas drug Benznidazole with pharmaceutics excipients

Context: Benznidazole (BNZ) is an antiparasitic with trypanocidal properties for the etiological treatment of Chagas disease since 1973. Monitoring the stability of this drug is one of the most effective methods of assessment, forecasting and prevention of problems related to quality product.

Objective: To investigate the direct and indirect photodegradation of BNZ and to evaluate the interference of the excipients used in the forms dosage solid as well as to shed light on the chemical structure of the degradation products obtained.

Materials and methods: To perform this work we adopted the “ICH Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products Q1B” (Guideline Q1B). We used benzonidazole (BNZ) (N-benzil-2-(2-nitroimidazol-1-il) acetamide) (LAFEPE®, Recife, Brazil) and various excipients; beyond high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and mass spectrometry/mass spectrometry (MS/MS). The indirect photodegradation of BNZ was carried out using physical mixtures with 13 pharmaceutical excipients commonly used in the preparation of solid dosage forms.

Results: HPLC and MS/MS techniques were selected for the identification of two photoproducts (PPs) and photoreactions found in direct and indirect tests with the microcrystalline cellulose, considered a critical excipient.

Discussion: Despite variations in the infrared spectrometry, differential scanning calorimetry and differential thermogravimetry curves, these techniques are not conclusive since the study of photodegradation of the drug caused decay of 30%, according to the ICH.

Conclusions: The results show that BNZ only undergoes direct photodegradation, since no new PPs were found for a combination of the drug and excipients.     

Improvement of bone microarchitecture in methylprednisolone induced rat model of osteoporosis by using thiolated chitosan-based risedronate mucoadhesive film

Objective: In this study, we investigated the potential of thiolated chitosan-based mucoadhesive film, loaded with risedronate sodium in the treatment of osteoporosis.

Significance: Risedronate sodium is a bisphosphonate derivative having very low bioavailability when administered through the oral route. Moreover, the adverse effects associated with the drug when administered through GIT necessitate an alternative and feasible route which can improve its bioavailability and therapeutic efficacy.

Methods: Thiolation of chitosan was interpreted by different analytical techniques. The mucoadhesive films were prepared by the solvent evaporation method and evaluated for drug content analysis, swelling degree, mucoadhesive parameters, and permeation characterization. For the screening of preclinical efficacy and pharmacodynamic parameters, a methylprednisolone induced osteoporotic rat model was used. The trabecular microarchitecture and biochemical markers were evaluated for determination of bone resorption.

Results: The different analytical characterization of synthesized thiolated chitosan revealed that chitosan was successfully incorporated with thiol groups. The formulation containing 2:1 ratio of thiolated chitosan and HPMC-4KM was found to have the maximum swelling degree, mucoadhesive strength with a good force of adhesion and better in vitro permeability compared to the marketed formulation. With respect to trabecular microarchitecture, the drug-loaded film formulation showed superior and promising results. Furthermore, the film formulation also improved the serum level of biomarkers better than the marketed formulation.

Conclusions: The results significantly suggest that risedronate loaded novel mucoadhesive film formulation could be a logical approach in the therapeutic intervention of osteoporosis.     

Efficacy,safety and mechanism of HP-β-CD-PEI polymers as absorption enhancers on the intestinal absorption of poorly absorbable drugs in rats

Context: Oral bioavailability of some hydrophilic therapeutic macromolecules was very poor, thus leading to their limited application in clinic.

Objective: To investigate the efficacy, safety and mechanism of HP-β-CD-PEI polymers on the intestinal absorption of some poorly absorbable drugs in rats.

Methods: Effects of HP-β-CD-PEI polymers on the intestinal absorptions of drugs were investigated by an in situ closed loop method in rats. The safety of HP-β-CD-PEI polymer was evaluated by measurement of lactate dehydrogenase (LDH) activity and amount of protein released from rat intestinal perfusate. The absorption enhancing mechanisms were explored by the measurement of zeta potential, transepithelial electrical resistance (TEER) and in vitro transport of FD4 (a paracellular marker) across rat intestinal membranes, respectively.

Results: HP-β-CD-PEI polymers, especially HP-β-CD-PEI₁₈₀₀, demonstrated excellent absorption enhancing effects on drug absorption in a concentration-dependent manner and the enhancing effect was more efficient in the small intestine than that in the large intestine. Five percent (w/v) HP-β-CD-PEI₁₈₀₀ obviously decreased the TEER, accompanied with increase in the intestinal transport of FD4, indicating that absorption enhancing actions of HP-β-CD-PEI polymers were possibly performed by loosening tight junctions of intestinal epithelium cells, thereby increasing drug permeation via a paracellular pathway. A good liner relationship between absorption enhancing effects of HP-β-CD-PEI polymers and their zeta potentials suggested the contribution of positive charge on the surface of these polymers to their absorption enhancing effects.

Conclusion: HP-β-CD-PEI polymers might be potential and safe absorption enhancers for improving oral delivery of poorly absorbable macromolecules including peptides and proteins.     

Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids

Objective: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA).

Significance: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development.

Method: The relative stability was determined from the preferentially formed cocrystals under various conditions.

Result: Cocrystal of APAP–OXA was more stable than that of APAP–MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP–MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP–OXA was more stable in aprotic solvents because the APAP–OXA with low-solubility product precipitated.

Conclusions: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network.     

The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study

Objective: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets’ critical quality attributes (CQA).

Significance: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues.

Methods: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU.

Results: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading.

Conclusions: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API’s content and uniformity when compared to industrial gravitational transfer.