Presence Of HPMC Research Articles

Three-Dimensional-Printed Oral Films Based on LCD: Influence Factors of the Film Printability and Received Qualities.

As an oral mucosal drug delivery system, oral films have been of wide concern in recent years because of their advantages such as rapid absorption, being easy to swallow and avoiding the first-pass effect common for mucoadhesive oral films. However, the currently utilized manufacturing approaches including solvent casting have many limitations, such as solvent residue and difficulties in drying, and are not suitable for personalized customization. To solve these problems, the present study utilizes liquid crystal display (LCD), a photopolymerization-based 3D printing technique, to fabricate mucoadhesive films for oral mucosal drug delivery. The designed printing formulation includes PEGDA as the printing resin, TPO as the photoinitiator, tartrazine as the photoabsorber, PEG 300 as the additive and HPMC as the bioadhesive material. The influence of printing formulation and printing parameters on the printing formability of the oral films were elucidated in depth, and the results suggested that PEG 300 in the formulation not only provided the necessary flexibility of the printed oral films, but also improved drug release rate due to its role as pore former in the produced films. The presence of HPMC could greatly improve the adhesiveness of the 3D-printed oral films, but excessive HPMC increased the viscosity of the printing resin solution, which could strongly hinder the photo-crosslinking reaction and reduce printability. Based on the optimized printing formulation and printing parameters, the bilayer oral films containing a backing layer and an adhesive layer were successfully printed with stable dimensions, adequate mechanical properties, strong adhesion ability, desirable drug release and efficient in vivo therapeutic efficacy. All these results indicated that an LCD-based 3D printing technique is a promising alternative to precisely fabricate oral films for personalized medicine.

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated β-Cyclodextrin Solid Dispersion.

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-β-CD) and acetylated (Ac-β-CD) β-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-β-CD as compared to Me-β-CD was revealed. The solid dispersion of BCL with Ac-β-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-β-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-β-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers—polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)—were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-β-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-β-CD (HPMC), BCL/Ac-β-CD (PVP), BCL/Ac-β-CD (buffer), and the BCL/Ac-β-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-β-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing.

Partitioning of surfactant into drug-rich nanodroplets and its impact on drug thermodynamic activity and droplet size

The excipients present in an amorphous solid dispersion (ASD) are essential functional additives that ultimately influence the drug release performance and absorption. Herein, the effect of a polymer, hypromellose (HPMC), and three chemically diverse surfactants, sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), and polyoxyethylene sorbitan monooleate (Tween 80, Tween), on the size and stability of the colloidal ketoprofen (KTP)-rich phase generated by liquid-liquid phase separation was evaluated. In addition, the impact of the excipients on the thermodynamic activity of KTP at concentrations in excess of the amorphous solubility was evaluated. Dynamic light scattering measurements showed that using surfactant alone did not effectively suppress coarsening of the KTP-rich phase. In contrast, the combined use of surfactant and HPMC maintained the KTP-rich droplet size at around 200 nm, which was smaller than in HPMC solutions without surfactant. Solution nuclear magnetic resonance spectroscopy revealed that HPMC distributed into the KTP-rich phase, leading to a reduced thermodynamic activity of KTP, and a consequent decrease in the maximum achievable aqueous phase concentration. Moreover, substantial amounts of both CTAB and Tween distributed into the KTP-rich phase from the aqueous phase, while SDS remained predominantly in the aqueous phase. The combined use of HPMC with CTAB or Tween resulted in a further decrease in the thermodynamic activity of KTP relative to in the presence of HPMC alone, due to the mixing of both HPMC and surfactant with the KTP-rich phase. In contrast, the addition of SDS did not reduce the thermodynamic activity of KTP because of the limited distribution of SDS into the KTP-rich phase. A reduction in KTP thermodynamic activity translated to a decreased supersaturation and hence a reduction in the maximum achievable membrane flux. The present study illustrates the complex effects of surfactant and polymer on drug thermodynamic activity, factors which should be considered when optimizing ASD formulations to maximize oral drug absorption. Ideally, excipients that do not substantially impact drug thermodynamic activity should be selected, in particular for drugs where achieving high supersaturation is critical to drive their absorption.

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study\u2014Hypromellose (HPMC)

Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Presence of HPMC affected drug solubility according to the physicochemical properties of studied compounds. The possible combined effects of polymer adsorption (drug shielding effect) or the formation of a polymeric viscous layer around drug particles may have retarded drug dissolution leading to reduced apparent solubility of highly soluble and/or highly ionized compounds and were pronounced mainly at early time points. Increase in the apparent solubility of poorly soluble low ionized drugs containing a neutral amine group was observed which may relate to enhanced drug solubilization or reduced drug precipitation. The use of multivariate data analysis confirmed the importance of drug physicochemical properties on the impact of excipients on drug apparent solubility and revealed that changes in HPMC material properties or amount may not be critical for oral drug performance when HPMC is used as a binder. The construction of a roadmap combining drug, excipient, and medium characteristics allowed the identification of the cases where HPMC presence may present risks in oral drug performance and bioavailability.

Tadalafil–Malonic Acid Cocrystal: Physicochemical Characterization, pH-Solubility, and Supersaturation Studies

The purpose of this study was to enhance the solubility and dissolution of a poorly water-soluble drug, tadalafil (TDF), by cocrystal formation with malonic acid (MOA), to characterize the cocrystal structure and to quantify the cocrystal solution behavior. The crystal structure revealed a 1:1 stoichiometry, wherein the TDF molecules form a double layered structure through N–H···O═C interactions linked to a catemeric chain of MOA molecules via O–H···O hydrogen bonds. Cocrystal solubility advantage (SA defined as Scocrystal/Sdrug) or supersaturation index was determined from eutectic point measurements to be 102 to 129 in the pH range of 1 to 3. Cocrystal dissolution generated supersaturation levels (Cmax/Sdrug) of 30 in buffer and 120 in the presence of a nucleation inhibitor, HPMC. The amorphous form of TDF generated supersaturation three times lower than cocrystal in buffer, and not significantly different from cocrystal in the presence of HPMC. Thus, supersaturation index is a valuable metric for asses...

Design and Development of Crystallo-co-agglomerates of Ritonavir for the Improvement of Physicochemical Properties.

The aim of the present study was to obtain CCA of ritonavir to improve the solubility, dissolution rate, and other physicochemical properties. Ritonavir agglomerates were prepared using the CCA technique. Acetone-water containing HPMC K-15, PEG-6000, PVP K-30 was used as the crystallization medium. The agglomerates were evaluated for saturation solubility, micromeritic properties, yield, and drug content. The agglomerates were also characterized using FTIR, DSC, XRPD and SEM. The growth of particle size and the spherical form of the agglomerates resulted in the formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to the fragmentation that occurred during compression. DSC and XRD studies showed that ritonavir particles crystallized in the presence of HPMC, PEG-6000, PVP K-30 and diluents did not undergo structural modifications. The solubility and dissolution rate of ritonavir agglomerates were improve compare to pure ritonavir. CCA was successfully applied to improve the physicochemical properties of ritonavir.

Formulation of clarithromycin floating microspheres for eradication of Helicobacter pylori

The aim of this study was to develop floating microspheres for gastroretentive delivery of clarithromycin for eradication of Helicobacter pylori. The microspheres were prepared by solvent evaporation using ethyl cellulose (EC) at different weight ratio with clarithromycin with hydroxypropyl methyl cellulose (HPMC E5) acting as secondary polymer. The emulsifier employed either polyvinylpyrrolidone (PVP) or polyvinyl alcohol (PVA). The microspheres were evaluated for floatation, drug entrapment and release, particle size, shape and surface morphology. The physical form of clarithromycin was monitored using FTIR, DSC and X-ray diffraction. The microspheres were in micron range with particle size reducing when replacing PVP with PVA. Further size reduction was recorded in presence of HPMC. The entrapment efficiency increased at high EC concentration especially in presence of HPMC. Immediate floatation was seen with at least 56% of the particles remaining on the surface after 8 h. Physical characterization reflected amorphousization or solubilization of clarithromycin after entrapment in the microspheres. The release pattern followed Higuchi matrix kinetic model in most formulations except those containing low concentration of EC or those containing high HPMC content with HPMC increasing the rate of drug release. The study presented floating microspheres with different release pattern depending on the composition.

Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%–0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.

Stearic acid crystals stabilization in aqueous polymeric dispersions

In wet granulation processes, coatings or binders generally consist of mixtures of various raw materials that confer or enhance specific properties to the final product. Typically, a coating solution is composed of water, film forming polymer (such as hydroxypropyl-methylcellulose, HPMC) and filler (such as stearic acid, SA).One of the important issues in wet granulation processes is the stability of the aqueous coating (or binder) dispersion. An unstable dispersion results in the agglomeration of the colloidal particles, thereby affecting the film coating properties and eventually the coating process.In this study, we use dissipative particle dynamics (DPD) to elucidate the structure of aqueous colloidal formulations. DPD is a coarse-grained molecular dynamics simulation method where the materials are described as a set of soft beads interacting according to the Flory–Huggins (1942) model. The DPD simulation results are compared to experimental results obtained by Cryogenic-SEM and particle size distribution analysis.It is shown from the DPD simulation results that the HPMC polymer is able to form a layer that covers SA particles and thus produces stable colloids. Microcrystalline cellulose (MCC) also covers SA agglomerate but it is not able to diffuse inside its inner core. The agglomerate structure is characterized via the density distribution and the polymer chain end-to-end distance.Experimental results show similar trends; particle size distribution analysis shows that in the presence of HPMC, the majority of SA particles are below 1μm in diameter, also MCC is able to prevent the formation of big SA agglomerates and may be a better stabilizing agent than HPMC. SEM images reveal that HPMC surrounds SA agglomerates with a hatching textured film and anchors on their surface.

Structure of aqueous colloidal formulations used in coating and agglomeration processes: Mesoscale model and experiments

In coating and agglomeration processes, the properties of the final product, such as solubility, size distribution, permeability and mechanical resistance, depend on the process parameters and the binder (or coating) solution properties. These properties include the type of solvent used, the binder composition and the affinity between its constituents.In this study, we used mesoscale simulations to investigate the structure of agglomerates formed in aqueous colloidal formulations used in coating and granulation processes. The formulations include water, a film forming polymer (Hydroxypropyl-methylcellulose, HPMC), a hydrophobic filler (Stearic acid, SA) and a plasticizer (Polyethylene glycol, PEG). For the simulations, dissipative particle dynamics (DPD) and a coarse-grained approach were used. In the DPD method, the materials are described as a set of soft beads interacting according to the Flory–Huggins model. The repulsive interactions between the beads were evaluated using the solubility parameter (δ) as input, where δ was calculated by all-atom molecular dynamics. The DPD simulation results were compared to experimental results obtained by cryogenic-SEM and particle size distribution analysis.DPD simulation results showed that the HPMC polymer is able to adsorb in depth into the inner core of SA particle and covers it with a thick layer. We also observed that the structure of HPMC-SA mixture varies under different amounts of SA. For high amounts of SA, HPMC is unable to fully stabilize SA. Affinity between the binder materials was deduced from the DPD simulations and compared with Jarray et al. (2014) theoretical affinity model.Experimental results presented similar trends; particle size distribution analysis showed that for low percentage of SA (below 10% w/w) and in the presence of HPMC, the majority of SA particles are below 1μm in diameter. Cryogenic-SEM images reveal that SA crystals are covered and surrounded by HPMC polymer. SA crystals remain dispersed and small in size for low percentages of SA.

Insights into the Role of Polymer-Surfactant Complexes in Drug Solubilisation/Stabilisation During Drug Release from Solid Dispersions

To evaluate the role of polymer-surfactant interactions in drug solubilisation/stabilisation during the dissolution of spray-dried solid dispersions and their potential impact on in vivo drug solubilisation and absorption. Dissolution/precipitation tests were performed on spray-dried HPMC-Etravirine solid dispersions to demonstrate the impact of different surfactants on the in vitro performance of the solid dispersions. Interactions between HPMC and bio-relevant and model anionic surfactants (bile salts and SDS respectively) were further characterised using surface tension measurements, fluorescence spectroscopy, DLS and SANS. Fast and complete dissolution was observed in media containing anionic surfactants with no drug recrystallisation within 4 h. The CMCs of bile salts and SDS were dramatically reduced to lower CACs in the presence of HPMC and Etravirine. The maximum increases of the apparent solubility of Etravirine were with the presence of HPMC and SDS/bile salts. The SANS and DLS results indicated the formation of HPMC-SDS/bile salts complexes which encapsulated/solubilised the drug. This study has demonstrated the impact HPMC-anionic surfactant interactions have during the dissolution of non-ionic hydrophilic polymer based solid dispersions and has highlighted the potential relevance of this to a fuller understanding of drug solubilisation/stabilisation in vivo.

In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: Complexation with hydroxypropyl-β-cyclodextrin in the presence of HPMC

Carbamazepine (CBZ)–hydroxypropyl-β-cyclodextrin (HP-β-CD) complex in the presence of HPMC was prepared and characterized by differential scanning calorimetry (DSC) and X-ray diffractometer intended for improving the dissolution rate of CBZ. The phase-solubility method was used to investigate the effect of HP-β-CD and HPMC on the solubility of CBZ. Tablets of the resulting complex were prepared using direct compression method and the bioavailability was evaluated in beagle dogs using a UPLC/MS/MS method. The results showed solubility of CBZ was increased up to 95 times by complexation with HP-β-CD in the presence of 0.1% HPMC. The results of DSC and X-ray diffraction proved a formation of complex between CBZ and HP-β-CD. Dissolution rate of CBZ was notably improved from complex tablets with more than 97.39% released within 10 min; whereas for the commercial tablets, around 60% was released within 30 min. Using commercial tablets as the reference formulation, the bioavailability of complex tablets was considerably increased by 1.5-fold ( P < 0.05) and T max was reduced to 0.88 h compared with 1.25 h for commercial tablets. Furthermore, a lower inter-subject variability (49.9%) was observed compared with that of the commercial tablets (39.7%). It is evident from the results herein that complexation with HP-β-CD in the presence of HPMC is a feasible way to prepare a rapidly acting and better absorbed CBZ oral product.

Dissolution enhancement of gliclazide using in situ micronization by solvent change method

Gliclazide (GL) is a second-generation sulphonylurea, widely used for the treatment of non-insulin dependent diabetes mellitus. The low water-solubility of GL leads to a low dissolution rate and variable bioavailability. The aim of this study was to enhance the dissolution rate of GL by the preparation of micron-sized particles using a solvent change method. The in situ micronization process was carried out using solvent change method in the presence of HPMC or Brij 35 (0.05 or 0.1 g) as stabilizing agents. GL (0.5 or 1 g) was dissolved in acetone and the stabilizing agent in water (as non-solvent). The non-solvent was poured rapidly into the drug solution under stirring at 26,000 rpm by an ultra-homogenizer, and the resultant was freeze-dried. The crystalline shape of GL changed from rod-shape to diamond- or cube-shape. The FTIR and DSC results showed no interaction between the drug and the stabilizers. Presence of sharp peaks in the XRD diffractograms of microcrystals with 10 times smaller height than untreated crystals indicates that a crystalline habit modification has occurred in the microcrystals without any polymorphic changes. The particle size was reduced about 50 times and the dissolution efficiency of GL at 15 min (DE 15%) was increased about 4 times.

In situ cross-linking of sodium alginate with calcium and aluminum ions to sustain the release of theophylline from polymeric matrices

Small matrices of calcium alginate or aluminium alginate have been investigated as possible controlled release systems for drugs. The objective of the present study was to sustain the release of theophylline from alginate matrices using different concentrations of aluminium chloride and calcium chloride in presence and absence of HPMC. Tablets containing differing concentrations of aluminium and calcium chloride were produced and the release rate of theophylline was tested using the basket dissolution apparatus over 8 h. Increasing amounts of aluminium chloride from 0.0001 to 0.00068 moles decreased the release of theophylline from 95.1 ± 0.27 to 29.5 ± 1.5, indicating a significant effect of aluminium ions on a reduction in the release rate of theophylline from sodium alginate matrices. In the case of matrices containing different concentrations of calcium ions, as the concentration of calcium chloride increased, the release rate increased to an optimum then declined after this. This was due to insufficient calcium ions being available to cross-link with the sodium alginate to form an insoluble gel. The effect of aluminium ions, as this is a trivalent ion compared to calcium, which is a divalent ion, aluminium ions are able to decrease the release rate with a smaller concentration compared to calcium ions. The results also showed that the presence of HPMC caused a reduction in release rate of theophylline from alginate matrices containing calcium chloride. Whereas, in the case of alginate matrices containing aluminium chloride the release rate of theophylline increased in presence of HPMC. For comparing the dissolution data, dissolution efficiency (DE) was used. The values of DE are consistent with the dissolution data. The results show that within a formulation series, DE values generally decrease when the cation concentration increases and this criterion can be used to describe the effect of calcium and aluminium ions on the release behaviour of theophylline from polymeric matrices.

A novel powder coating process for attaining taste masking and moisture protective films applied to tablets

A novel powder coating process was developed for the application of taste masking and moisture protective films on tablets while avoiding the use of solvents or water. The coalescence of particles to form a polymeric film was investigated through studies of dry powder layering of micronized acrylic polymer (E PO) to produce free films. Theophylline containing tablets were coated with the same acrylic polymer in a laboratory scale spheronizer using a powder coating technique. The dry powder layer delayed the onset of drug release in pH 6.8 medium, depending on the coating level, while no delay was observed in pH 1.0 medium. The presence of hydrophilic polymers in the acrylic coating layer decreased the lag time for drug release in pH 6.8 medium, while only the presence of HPMC in the film slowed the drug release rate in acidic medium. The dry coating process was demonstrated to be a reliable alternative to solvent or aqueous film coating technologies for applying taste masking and moisture protective film coats onto compressed tablets. A controlled drug release profile was achieved in pH 6.8 media.

Studies of model macroscopic-defect-free materials. Part 2.—Microstructure and open porosity in the system 4CaO·Al2O3· Fe2O3–4CaO·3Al2O3· SO3–hpmc–H2O

Model macroscopic-defect-free materials (MDFs) representing selected compositions in the system 4CaO · Al2O3· Fe2O3–4CaO · 3Al2O3· SO3–hmpc–H2O have been investigated by means of electron microscopy and mercury intrusion porosimetry. ‘Smooth spatial flow’ of unreacted grains into an intergranular hydrated-aluminium-monosulfate-related (AFm-like) phase and rigid linkage of clinker phase–intergranular mass–solidified polymer are demonstrated. Solidification of an intergranular Afm–like phase in the presence of hpmc and pressure during syntheses causes partial elimination of pores; electron microscopy shows the remaining pores to be isolated at the micrometre level. Pore size distributions reveal the role of pressure in packing the pores with diameter r > 100 nm. Careful control of the mixing and pressing of reaction mixtures results in porosities in the range typical of MDFs. A scheme interrelating the atomic- and particle-level phenomena is outlined, and includes formation of Al(Fe)–O–C crosslinks between cement clinker and polymer.