Model Basic Drugs Research Articles

Utilizing the allyl-terminated copolymer methoxy(poly(ethylene glycol))-block-poly(jasmine lactone) in the development of amorphous solid dispersions: A comparative study of functionalized and non-functionalized polymer

Molecular interactions are crucial to stabilize amorphous drugs in amorphous solid dispersions (ASDs). Most polymers, however, have only a limited ability to form strong molecular interactions with drugs. Polymers tailored to fit the physicochemical properties of the drug molecule to be incorporated, for instance by allowing the incorporation of specific functional groups, would be highly sought-for in this regard. For this purpose, the novel allyl-terminated polymer methoxy(polyethylene glycol)-block-poly(jasmine lactone) (mPEG-b-PJL) has been synthesized and functionalized to potentially enhance specific drug-polymer interactions. This study investigated the use of mPEG-b-PJL in ASDs, using carvedilol (CAR), a weakly basic model drug. The findings revealed that the acidic functionalized form of the polymer (mPEG-b-PJL-COOH) indeed established stronger molecular interactions with CAR compared to its non-functionalized counterpart mPEG-b-PJL. Evaluations on polymer effectiveness in forming ASDs demonstrated that mPEG-b-PJL-COOH outperformed its non-functionalized counterpart in miscibility, drug loading ability, and stability, inferred from reduced molecular mobility. However, dissolution tests indicated that ASDs with mPEG-b-PJL-COOH did not significantly improve the dissolution behaviour compared to amorphous CAR alone, despite potential solubility enhancement through micelle formation. Overall, this study confirms the potential of functionalized polymers in ASD formulations, while the challenge of improving dissolution performance in these ASDs remains an area of further development.

Amorphous Solid Dispersions Layered onto Pellets—An Alternative to Spray Drying?

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance.

Improving drug release rate, drug-polymer miscibility, printability and processability of FDM 3D-printed tablets by weak acid-base interaction

Slow drug release, low drug-polymer miscibility, poor printability of polymers used, and high processing temperature are major challenges in developing FDM 3D-printed tablets. These challenges were addressed in this investigation by having a model basic drug, haloperidol (mp: 151.5 °C), interact with a weak acid, malic acid (mp: 130 °C), during the melt extrusion of formulations into filaments used for 3D-printing. Malic acid was selected as it was previously reported that it did not form any crystalline salt with haloperidol but its addition to aqueous media could greatly increase the solubility of haloperidol from ∼ 1 µg/mL to > 1 g per mL of water by acid-base supersolubilization. Concentrated solutions of haloperidol-malic acid mixtures produced amorphous materials upon drying. It has been observed in the present investigation that similar interaction between haloperidol and malic acid may also occur in the absence of water. Upon heating, haloperidol-malic acid mixtures at 1:1 and 1:2 molar ratios turned amorphous starting at ∼ 50 °C, which is much below the melting point of either component. When Kollidon® VA64, a brittle and non-printable polymer, was used as the polymeric carrier, the acid-base interaction greatly reduced the melt viscosity of haloperidol-malic acid-Kollidon® VA64 ternary mixtures. Consequently, melt extrusion of filaments and printing of tablets using such mixtures could be performed at much lower temperatures than those with haloperidol-Kollidon® VA64 binary mixtures. The filaments containing 15 % and 30 % haloperidol along with malic acid and Kollidon® VA64 could be printed into tablets at relatively low temperatures of 125 and 100 °C, respectively, thus making Kollidon® VA64 not only printable but also doing so at low temperatures. Up to 50 % w/w drug load in filaments was achieved without any crystallization of haloperidol or malic acid. Drug release at pH 2 and 6.8 from printed tablets with 100 % infill was 80 % in < 30 min. Thus, the acid-base interaction can successfully resolve multiple development challenges encountered with FDM 3D-printed tablets.

Nortriptyline Hydrochloride Solubility-pH Profiles in a Saline Phosphate Buffer: Drug-Phosphate Complexes and Multiple pHmax Domains with a Gibbs Phase Rule "Soft" Constraints.

The solubility of a model basic drug, nortriptyline (Nor), was investigated as a function of pH in phosphate and/or a chloride-containing aqueous suspension using experimental practices recommended in the previously published "white paper" (Avdeef et al., 2016). The pH-Ramp Shake-Flask (pH-RSF) method, introduced in our earlier work (Marković et al., 2019), was applied. An improved and more detailed experimental design of the Nor solubility measurement allowed us to exploit the full capacity of the pH-RSF method. Complex equilibria in the aqueous phase (cationic and anionic complex formation between Nor and the phosphate) and solid-phase transformations (Nor free base, 1:1 Nor hydrochloride salt, 1:1 and 1:2 Nor phosphate salts) were characterized by a detailed analysis of the solubility measurements using the computer program pDISOL-X. The solid phases were characterized by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analyses. The results of the present investigation illustrate the influence of competing counterions, such as buffering agents, complexing agents, salt coformers, tonicity adjusters, and so forth, on the aqueous solubility of drugs and interconversion of salts. Careful attention given to these factors can be helpful in the formulation of drug products.

Stabilising disproportionation of lipophilic ionic liquid salts in lipid-based formulations

Lipid based formulations (LBFs) can enhance oral bioavailability, however, their utility may be restricted by low drug loading in the formulation. Converting drugs to drug-ionic liquids (drug-ILs) or lipophilic salts can significantly increase lipid solubility but this approach is complicated in some cases by salt disproportionation, leading to a reduction in solubility and physical instability. Here we explore the physical stability of the weakly basic model drug, cinnarizine (CIN), when paired with a decanoate counterion (Dec) to form the drug-IL, cinnarizine decanoate (CIN.Dec). Consistent with published studies of salt disproportionation in aqueous solution, weakly acidic counterions such as Dec lead to the generation of drug-IL lipid solutions with pHs below pHmax. This leads to CIN deprotonation to the less soluble free base and precipitation. Subsequent studies however, show that these effects can be reversed by acidification of the formulation (either with excess decanoic acid or other lipid soluble acids), stimulating a pH shift to the salt plateau of CIN.Dec and the formation of stable lipid solutions of CIN.Dec. Altering formulation pH to more acidic conditions, therefore stabilises drug-ILs formed using weakly acidic lipophilic counterions, and is a viable method to promote formulation stability via inhibition of disproportionation of some drug-ILs.

Molecular recognizable ion-paired complex formation between diclofenac/indomethacin and famotidine/cimetidine regulates their aqueous solubility

This study focused on the physicochemical interactions between acidic and basic drugs in aqueous solutions. Their ion pair interactions were evaluated in an in vitro study. The model non-steroid anti-inflammatory drugs (NSAIDs), indomethacin (INM) and diclofenac (DIC), were used as acidic and hydrophobic drugs, whereas cimetidine (CIM), famotidine (FAM), and imidazole (IMD) were used as basic additives with heterocyclic moieties. The drug mixtures were evaluated by thermal analysis, dissolution test, nuclear magnetic resonance (NMR) spectroscopy, and mass spectroscopy. The fusion enthalpy of DIC-CIM, INM-CIM, and INM-arginine (ARG) sample was calculated based on melting temperature transformation. The DIC mixture with CIM, IMD, antipyrine (ANT), and ARG showed enhanced solubility, whereas the DIC-FAM mixture sample showed a decreased solubility. Electrospray ionization mass spectroscopy was carried out to detect binary mixtures. The interactions in DIC-FAM mixture sample were found between the carboxyl group of DIC and the amine groups of FAM by NMR. These findings were suggested that DIC-FAM mixture samples construct ion pair complexes based on the theory of Bjerrum. Moreover, the acid model drug and basic model drug also can be constructed 1:1 complexes that affects their solubility in the solvent of water type.

An investigation on the effect of filtration and dilution of biological samples on electromembrane extraction efficiency: Determination of basic drugs in plasma and urine samples

AbstractIn the present work, the impact of dilution and filtration of biological samples (plasma and urine) using ultra‐centrifugal filters were analytically assessed as pretreatment steps before the electromembrane extraction. Pseudoephedrine, lidocaine, propranolol, and ketoconazole were chosen as the basic model drugs. They were analyzed by using high‐performance liquid chromatography coupled with an ultraviolet‐visible detector after the extraction process. In this way, the type of filter and sample dilution order were evaluated in addition to the method's figures of merit. Hence, purification of the biological samples via ultra‐centrifugal filters results in a successful electromembrane extraction procedure in the presence of high applied voltages (≥300 V). It brings notable augmentation in the extraction recoveries. As a result, a reduction in the amount of electrical current of the extraction system (17.0–30.0 µA for plasma and 23.0–33.0 µA for urine) and acceptable repeatability (4.6–12.9%) were observed. In the water, linearity was attained between 25.0 and 1000.0 ng/mL; besides, limits of quantification were in the range of 10.0–25.0 ng/mL, and limits of detection were between 3.0 and 7.5 ng/mL.

Preparation and Evaluation of Ternary Polymeric Blends for Controlled Release Matrices Containing Weakly Basic Model Drug.

The objective of this study was to evaluate the suitability of a ternary mixture of smart polymers comprised of Eudragit®E100, Eudragit®L100, and sodium alginate to serve as a carrier for sustained drug release for weakly basic drugs. The model drug chosen in this part of the study is Metronidazole. Matrix tablet formulations were prepared by either direct compression or by wet granulation. Dissolution studies were conducted using USP XXΠ rotating paddle apparatus in three different consecutive stages (pH 1.2, 4.8, and 6.8). Tablets made of low to intermediate proportions of sodium alginate and approximately equal proportions of Eudragit®E100 and Eudragit®L100 were found to have a significant modification of drug release rates. Thus, indicating a potential for controlling the drug release for 12 hours depending on polymers ratios in the formulation. The ratio of sodium alginate to total Eudragit® polymers and the ratio of Eudragit®E100 to Eudragit®L100 within the ternary polymeric composition were found critical in determining the controlled release performance. Results of swelling studies were in agreement with the dissolution behaviors of the tablets. The findings suggest the significance of the ternary polymeric compositions in controlling the release of a weakly basic drug, Metronidazole.

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention-A Combined In Vivo/In Silico Approach Based on Four Model Drugs.

Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.

Inside gel electromembrane extraction: A novel green methodology for the extraction of morphine and codeine from human biological fluids

In this work, a new mode of gel-electromembrane extraction (G-EME), called “inside” gel-EME (IG-EME) is proposed for the extraction of morphine and codeine as model basic drugs from complex biological samples. Here, an aqueous media that was captured inside the agarose gel membrane, acted as both gel membrane and the acceptor phase (AP) at the same time. In this regard, the membrane served as the separation filter (membrane) and supported liquid acceptor phase (SLAP) as well. With this new development, unwanted changes of the AP volume during the extraction, which is a common issue in the G-EME (due to electroendosmosis (EEO) phenomenon), was addressed properly. Briefly, the setup involved insertion of negative electrode inside the gel membrane and positive electrode into the donor phase (DP). Following that, the IG-EME was easily performed using optimal conditions (pH of the DP: 6.0; membrane composition (agarose concentration: 1% (w/v) in aqueous media with pH 3.0, and 15 mm thickness); voltage: 25 V; and extraction time: 30 min). After extraction, the agarose gel was withdrawn and centrifuged for 5 min with 12000 rpm, to disrupt its framework to release the “trapped aqueous AP” apart from the gel structure. The separated AP was finally injected into the HPLC-UV for the analysis. The limits of detection (LODs) and recoveries in this proposed method were obtained 1.5 ng mL−1 and 67.7 %–73.8 %, respectively. The system feasibility was examined by the quantification of model drugs in the real plasma and urine samples.

Sensitive determination of ketamine, methylphenidate, and tramadol in urine and wastewater samples by Porous Aromatic Framework-48 assisted electromembrane extraction coupled with ion mobility spectrometer

A Porous Aromatic Framework-48 with the nitro functional groups (PAF-48-NO2) has been introduced as a new porous structure for boosting electromembrane extraction efficiency followed by ion mobility spectrometer. We developed this method by immobilizing PAF-48-NO2 into the microporous polypropylene hollow fibers for the extraction of three model basic drugs including Ketamine, Methylphenidate and Tramadol with different polarities (log P: 3.35, 2.25, and 2.45, respectively). The best extraction condition was obtained as following: 2-nitro phenyl octyl ether as organic solvent containing 3.0 mg mL−1 of PAF-48-NO2 as sorbent, driving force of 180 V, extraction time of 20 min, pH of sample and acceptor solutions of 4.0 and 1.0, respectively, and stirring rate of 1000 rpm without any use of salt. The proposed PAF-48-NO2-electromembrane extraction method was found to be sensitive for the extraction of the model drugs in the optimized condition with good linearties (>0.998), limit of detection (1.5–3.6 ng mL−1), and high repeatability relative standard deviation 2.5–3.9%. In addition, the extraction efficiency of the proposed PAF-48-NO2-electromembrane extraction method was higher than the classical electromembrane extraction method. Finally, the proposed method was successfully applied for the determination of Ketamine, Methylphenidate, and Tramadol in various spiked samples such as urine and wastewater samples.

Direct capillary electrophoresis analysis of basic and acidic drugs from microliter volume of human body fluids after liquid-phase microextraction through nano-fibrous membrane.

In the present work, a disposable microextraction device with a polyamide 6 nano-fibrous supported liquid membrane (SLM) is employed for the pretreatment of minute volumes of biological fluids. The device is placed in a sample vial for an at-line coupling to a commercial capillary electrophoresis instrument with UV-Vis detection (CE-UV) and injections are performed fully automatically from the free acceptor solution above the SLM with no contact between the capillary and the membrane. Up to 4-fold enrichment of model basic (nortriptyline, haloperidol, loperamide, and papaverine) and acidic (ibuprofen, naproxen, ketoprofen, and diclofenac) drugs is achieved by optimizing the ratio of the donor to the acceptor solution volumes (16 to 4 μL, respectively). The actual setup enables SLM extractions from less than a drop of sample and is suitable for pretreatment of scarce human body fluids. Two unique methods are reported for efficient clean-up and enrichment of the basic and acidic drugs from capillary blood (formed as dried blood spot), serum, and urine samples, which enable their determination at therapeutic and/or toxic levels. The hyphenation of the SLM extraction with CE-UV analysis provides good repeatability (RSD, 2.4-14.9%), linearity (r2, 0.988-1.000), sensitivity (LOD, 0.017-0.22 mg L-1), and extraction recovery (ER, 20-106%) at short extraction times (10 min) and with minimum consumption of samples and reagents. Graphical abstract.

Sugaring-out assisted electromembrane extraction of basic drugs from biological fluids: Improving the efficiency and stability of extraction system

In the current study, for the first time, the sugaring-out effect was assessed in a conventional electromembrane extraction (EME) system. Utilizing the sugars in the donor solution as green additives can result in production of a pioneering and influential EME mode. Sugaring-out assisted electromembrane extraction was combined with high-performance liquid chromatography (HPLC) to enhance the extraction of four basic model drugs (pseudoephedrine, lidocaine, propranolol, and ketoconazole). In this mode of EME, not only the transfer of analytes through the supported liquid membrane (SLM) was improved, but also the whole extraction system became more stable than the conventional one in the same voltage. The type and concentration of sugars were optimized in addition to the common experimental parameters influencing the EME, and figures of merit were also studied. Under the optimum conditions, repeatability (RSD%) was obtained in the range of 2.8–6.9% in the water, while RSD value was obtained in the range of 8.2–11.8% (n = 3) for conventional EME with the same state. The linearity range was also in the interval of 5.0–1000.0 ng mL-1 and limits of quantification and detection were in the ranges of 5.0–10.0 ng mL-1 and 1.5–3.0 ng mL-1, respectively, in the introduced EME. Extraction recoveries in the range of 41.2 and 80.8% were obtained resulting in enrichment factors in the range of 96–189. In light of such factor, new suggested EME mode was assessed in the real biological samples including human plasma and urine in order to prove the sugaring-out efficiency in EME systems.

The effect of membrane thickness on supported liquid membrane extractions in-line coupled to capillary electrophoresis for analyses of complex samples

The effect of membrane thickness on extraction performance was systematically examined in extractions through supported liquid membranes (SLM), which were in-line coupled to capillary electrophoresis (CE). Three porous polypropylene membranes with different thickness (25, 100 and 170 μm) were used as supports for SLM extractions of model basic drugs (nortriptyline, papaverine, haloperidol and loperamide) from complex samples. The analytes were transferred through the SLMs by a pH gradient and were in-line injected, separated and quantified using a commercial CE instrument with ultraviolet (UV) detection. Transfers of the model drugs through SLM decreased with the increased membrane thickness (in the order: 25 > 100 > 170 μm) and highest transfers were achieved for the thinnest membrane. Interferences from complex sample matrices were efficiently eliminated, moreover, impregnation of the 25 μm membrane required significantly reduced volume of organic solvent. Mechanical stability of the impregnated 25 μm membrane was excellent during in-line injections, which necessitated direct contact of CE separation capillary with the SLM. Repeatability of the hyphenated SLM-CE-UV method (using the 25 μm membrane) was lower than 11% (RSD values of peak areas) and calibration curves were strictly linear in 0.5–30 μg/mL concentration range (coefficients of determination ≥ 0.997). Transfers of the basic drugs from donor solutions (standard and undiluted human urine/plasma) through the SLMs ranged from 45 to 231% and limits of detection were between 0.02 and 0.15 μg/mL.

In-line coupling of supported liquid membrane extraction across nanofibrous membrane to capillary electrophoresis for analysis of basic drugs from undiluted body fluids.

Planar polyamide 6 nanofibrous membrane was for the first time used in direct coupling of supported liquid membrane (SLM) extraction to CE analysis. Disposable microextraction device with the nanofibrous membrane was preassembled and stored for immediate use. The membrane in the device was impregnated with 1 µL of 1-ethyl-2-nitrobenzene and the device was subsequently filled with 10 µL of acceptor solution (10 mM HCl) and 15 µL of donor solution (sample). The device was in-line coupled to CE system for selective extraction and direct injection, separation and quantification of model basic drugs (nortriptyline, haloperidol, loperamide and papaverine) from standard saline solutions (150mM NaCl) and from undiluted human body fluids (urine and blood plasma). Compared to standard polypropylene supporting material, the nanofibrous membrane demonstrated superior characteristics in terms of lower consumption of organic solvents, constant volumes of operational solutions, full transparency and possibility to preassemble the devices. Extraction parameters were better or comparable for the nanofibrous vs. the polypropylene membrane and the hyphenated SLM-CE method with the nanofibrous membrane was characterized by good repeatability (RSD ≤ 11.3%), linearity (r2 ≥ 0.9953; 0.5-20mg/L), sensitivity (LOD ≤ 0.4mg/L) and transfer (27-126%) of the basic drugs.

Effect of pH on weakly acidic and basic model drugs and determination of their ex vivo transdermal permeation routes

ABSTRACT The aim of the present study was to investigate the effect of donor pH on the transdermal permeability of the model drugs across rat skin and also to determine the major route of transport of the drugs. Weakly acidic drugs (partition coefficient) ibuprofen (3.6), aceclofenac (3.9), glipizide (1.9) and weakly basic drugs olanzapine (3.6), telmisartan (6.0), and sildenafil citrate (1.9) were selected for the study. The ex vivo permeation studies of these drugs at different donor pH (pH - 1.2, 4, 5, 6.8, 7.4, and 8) using Franz diffusion cell (area, 7.54 cm2) has shown a pH-dependent permeability. Among these drugs the weakly acidic drugs has shown higher permeation rates compared to the weakly basic drugs. The permeability coefficient and the distribution coefficient of the weakly basic drugs increased on increasing the pH whereas the weakly acidic drugs showed an inverse relation. The weakly basic drugs also showed an increase in permeation with increase in the fraction of unionized species indicating dominance of transcellular route of permeation. With an exception of sildenafil citrate, a weakly basic salt form of the drug which showed a high permeation value at pH 7.4 where 57% of the drug was unionized, indicating the involvement of both paracellular and transcellular route in its permeation.

Evaluation of the synergistic effect with amino acids for enantioseparation of basic drugs using capillary electrophoresis.

The synergistic effect of two acidic amino acids, aspartic and glutamic acid, on the electrophoretic enantioseparation of four basic drugs was evaluated in the BGE containing a CD and at different pHs. Chlorpheniramine, hydroxyzine, propranolol and tramadol were used as the basic model drugs. However, no enantioseparations were achieved with a BGE containing sole amino acid, but the combined use of an acidic amino acid and a CD showed improved enantioseparations (synergistic effect) compared with the single CD system. The results demonstrated that at optimized pH, the electrostatic interactions of the anionic amino acids with the positively charged basic drugs could result in a decrease of the analyte migration velocity and it consequently improved the enantioseparation. The effective parameters such as the amino acid and chiral selector type and concentration, buffer pH, applied voltage, and capillary temperature were optimized. Favorable enantiomeric resolution and migration times of the model drugs were achieved with a 100mM phosphate buffer solution (pH 3.0) containing 5.0mM HP-α-CD/HP-β-CD and 20mM aspartic acid with an 18kV applied voltage at 25°C. 1 H NMR experiments were also carried out in a mixture of an analyte and CD in the absence and presence of aspartic acid. The NMR results were consistent with the results obtained by CE which showed the synergistic effect of amino acid.

Development of Fast-Dissolving Amorphous Solid Dispersion of Itraconazole by Melt Extrusion of its Mixture with Weak Organic Carboxylic Acid and Polymer.

The purpose of this study was to explore the feasibilityof developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion. Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon®VA64, was melt extruded at 95°C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH1.2, followed by a change in pH to 5.5. Despite the high melting point of 168°C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98°C), and physically stable ASD was produced when the formulation was extruded at 95°C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon®VA64, was formed. Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water-soluble basic drugs.

Application of Guanidine Hcl to Improve Enantioseparation of a Model Basic Drug, Cetirizine, By Capillary Electrophoresis Using Sulfated Β-Cyclodextrin.

A common approach in resolving enantiomers of chiral basic drugs by capillary electrophoresis (CE) is to use cyclodextrins (especially their anionic derivatives) as chiral selector in the acidic buffer (pH ≤ 3) in normal or reversed (carrier) mode. Then, some organic modifiers are added to the buffer solution if the resolution is not satisfactory. In case of cetirizine (CTN), applying the same approach, i.e. a reversed mode capillary zone electrophoresis (CZE) method with an acidic buffer and sulfated-β-cyclodextrine (S-bCD) as chiral selector, was failed and no complete enantioseparation was achieved. Different organic modifiers, like urea and triethylamine HCl, were used to improve chiral resolution which led to partial resolution of the two peaks. Then, guanidine HCl at a concnetration of 100 mM was added to the running buffer and an acceptable resolution of the enantiomers of the drug was obtained. The method was successfully applied to determine optical purity of a levo-cetirizine (l-CTN) sample.

Withdrawn: Novel Ternary Polymeric Blends for Controlled Release Matrices Containing Weakly Basic Model Drug.

Ahead of Print article withdrawn by publisher.