Preparation and characterization of new sorbents based on molecularly imprinted polymers for selected steroids and uv filters

Molekulski obeleženi polimeri su funkcionalni materijali sa unapred definisanom selektivnošću ka određenom molekulu. Cilj ove disertacije bio je dobijanje i karakterizacija molekulski obeleženih polimera sa templatima iz klasa steroida (holesterol) i UV filtera (benzofenon-4). Sintetisano je nekoliko serija molekulski obeleženih polimera i njihovih neobeleženih analoga primenjujući nekovalentni pristup, tehnikom polimerizacije u masi. Dobijeni sorbenti su okarakterisani pomoću infracrvene spektroskopije, skenirajuće elektronske mikroskopije, fizisorpcijom azota, elementalnom analizom, kao i pomoću adsorpcionih izotermi. Na osnovu karakterizacije dobijenih polimera može se zaključiti da je proces obeležavanja za odabrane template uspešno izveden. Polimeri obeleženi holesterolom i benzofenonom-4 imaju veći kapacitet za vezivanje templata od neobeleženih analoga. Rezultati ispitivanja selektivnosti dobijenih polimera ukazuju da su dobijeni polimeri selektivni za vezivanje templata u odnosu na druga jedinjenja iz iste grupe. Ispitana je mogućnost primene dobijenih polimera za ekstrakciju benzofenona-4 iz vodenih rastvora. Pokušaji dobijanja molekulski obeleženih polimera za UV filtere na bazi ciklodekstrina, nisu, za sada, dali zadovoljavajuće rezultate.Molecularly imprinted polymers represent functional materials with predetermined selectivity towards chosen molecule. The goal of this dissertation was preparation and characterization of molecularly imprinted polymers with steroid templates (cholesterol) and UV filters (benzophenone4). Several series of imprinted polymers and their non-imprinted analogs were synthesized, applying non-covalent approach, by bulk polymerization. Prepared sorbents were characterized by infrared spectroscopy, scanning electron microscopy, nitrogen physisorption, elemental analysis and adsorption isotherms. Results show that imprinting process was successful. Polymers imprinted with cholesterol and benzophenone-4 as templates have higher binding capacities than corresponding nonimprinted analogs. Selectivity of imprinted polymers was tested, showing that imprinted polymers are selective towards template compared to similar compounds binding. The application of benzophenone-4 imprinted polymers for solid-phase extraction from aqueous solutions was examined. Preparation of imprinted polymers for UV filters based on cyclodextrins was not successful so far

pH-Dependent solubility profile of desipramine hydrochloride

pH-dependent solubility profile of Desipramine hydrochloride (Ds.HCl) was studied using pH-ramp shake flask method. First, the pH value of DsHCl stock solution in 0.15 M phosphate buffer was adjusted to 11.7 in order to minimize supersaturation effect. Then, the pH value in separate samples was adjusted downwards with HCl, to prepare solutions in the pH 1.7-11.7 region. After stirring (6 h) and sedimentation (18 h), PTFE (hydrophobic, pore size 0.22 µm) filters or centrifugation were used for phase separation. Concentration was measured using HPLC with UV/Vis detection. The computer program pDISOL-X was used for data processing and refinement of equilibrium constants. Different techniques were used for solid phase characterization

pH-Dependent solubility profile of desipramine hydrochloride

pH-dependent solubility profile of Desipramine hydrochloride (Ds.HCl) was studied using pH-ramp shake flask method. First, the pH value of DsHCl stock solution in 0.15 M phosphate buffer was adjusted to 11.7 in order to minimize supersaturation effect. Then, the pH value in separate samples was adjusted downwards with HCl, to prepare solutions in the pH 1.7-11.7 region. After stirring (6 h) and sedimentation (18 h), PTFE (hydrophobic, pore size 0.22 µm) filters or centrifugation were used for phase separation. Concentration was measured using HPLC with UV/Vis detection. The computer program pDISOL-X was used for data processing and refinement of equilibrium constants. Different techniques were used for solid phase characterization

Highly selective water-compatible molecularly imprinted polymers for benzophenone-4: Scientific paper

Molecularly imprinting technology was applied for preparing selec­tive sorbents for benzophenone-4 (BP4), an organic UV filter used in sun­screens and cosmetics. Several imprinted polymers were prepared by bulk polymerization, using BP4 as template. Combination of stability (mechanical and chemical), selectivity and robustness of the imprinted polymers with BP4 properties resulted in a successful imprinting process (imprinting factors in range 1.05–2.60). The prepared polymers were characterised by infrared spec­tro­scopy, elemental analysis, conductometric titrations and nitrogen physi­sorp­tion at 77 K. Adsorption capacities and selectivity towards 7 other organic UV filters (benzophenone-3, benzophenone-8, homosalate, butyl methoxydi­ben­zo­ylmethane, ethyl hexyl salicylate, ethyl hexyl p-dimethylamino benzoate and ethyl hexyl p-methoxycinnamate) were determined, proving high adsorption capacity and high selectivity for BP4 binding. The highest adsorption capacity was observed for 4-vinylpyridine/ethylene glycol dimethacrylate co-polymer prepared in dimethyl sulfoxide (1.108 mmol g-1). The imprinted polymer with the highest binding capacity was applied to solid phase extraction of BP4 from aqueous solutions with 98.5 % efficiency

pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides

The aim of this study was to examine solubility-pH behavior of desipramine structural analogues: imipramine and amitriptyline hydrochlorides. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow sedimentation, and oil forms make solubility determination extremely challenging. Oils which are more soluble than crystalline forms are formed in alkaline solutions (above pH 7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis detection. Different techniques were used for solid phase characterization. Solid phase characterization is particularly important in complicated systems like this

A novel method of molecular imprinting applied to the template cholesterol

A novel method is successfully tested for non-covalent imprinting. Conditions are used which practically exclude the formation of prepolymerization complexes. The template is cholesterol, and no so-called functional monomer is used. The polymers contain only an acrylic diester crosslinker. The porogen isopropanol prevents even hydrogen bonding between the template and the monomer in the prepolymerization solution. Despite of these apparently very disadvantageous conditions, appreciable imprinting factors for cholesterol and imprinted selectivity against some other steroids are observed, similar to other cholesterol MIPs with proven analytical usefulness

Study of equilibria in heterogeneous systems of tricyclic antidepressant amitriptyline

Cilj ovog rada bio je proučavanje ravnoteža u heterogenim sistemima tricikličnog antidepresiva amitriptilina (Am) koji sadrže hloride i/ili fosfate. Rastvorljivost Am u uslovima povećane jonske sile određena je pH–Ramp shake–flask metodom. Veća rastvorljivost Am u kiseloj sredini od očekivane, posledica je agregacije – analiza eksperimentalnih podataka pomoću programa pDISOL–XTM ukazuje na verovatno građenje pentamera Am5H5 5+. Kritična micelarna koncentracija i stepen disocijacije agregata određeni su primenom konduktometrijskih titracija. U baznoj sredini primećena je delimična degradacija Am. Eksperimentalno dobijeni podaci o rastvorljivosti biološki aktivnih supstanci i postojećim ravnotežama u heterogenim sistemima važni su u svim fazama dizajna i razvoja lekova.The aim of this work was to study the equilibria in tricyclic antidepressant amitriptyline (Am) heterogeneous systems containing chloride and/or phosphate ions. Solubility of Am in high ionic strength conditions was determined using pH–Ramp shake–flask method.1, 2 Higher solubility of Am than expected in an acidic media is a consequence of self-aggregation – pentamer formation (Am5H5 5+) according to pDISOL–XTM analysis. Critical micelle concentration and the degree of the aggregate dissociation were determined by conductometric titrations. Partial degradation of Am in alkaline suspensions was observed. Experimental studies of solubility as well as the existing equilibria in heterogeneous systems of biologically active compounds are important at all stages of drug design and development

Solubility-pH profile of desipramine hydrochloride in saline phosphate buffer: Enhanced solubility due to drug-buffer aggregates

Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the recently-published “white paper” (Avdeef et al., 2016). The computer program pDISOL-X was used to design the structured experiments (pH-RSF method), to process the data, and to refine the equilibrium constants. Low-to-high and high-to-low pH assays (using HCl, H 3 PO 4 , or NaOH to adjust pH) were performed on phosphate-buffered (0.12‑0.15 M) saturated solutions of DsHCl in the pH 1.3–11.6 range. After equilibration (stirring 6 h, followed by 18 h stir-free sedimentation), filtration or centrifugation was used for phase separation. Concentration was measured using HPLC with UV/VIS detection. The 2:1 drug-phosphate solubility product (K sp 2:1 = [DsH + ] 2 [HPO 4 2− ]) was determined from data in the pH 4–9 region. The free base of desipramine was prepared and used to determine the K sp 1:1 ([DsH + ][H 2 PO 4 − ]) in chloride-free acidified suspension. In addition, phosphate-free titrations were conducted to determine the intrinsic solubility, S 0 , and the 1:1 drug-chloride solubility product, K sp DsH [rad] Cl = [DsH + ][Cl − ]. Under the assay conditions, only the phosphate-free solutions showed some supersaturation near pH max 8.0. In phosphate-containing solutions, pH max was indicated at higher pH (8.8–9.6). Oils mixed with solids were observed to form in alkaline solutions (pH > 11). Notably, soluble drug-phosphate complexes appeared to form below pH 3.9 and above pH max in saturated phosphate‑containing saline solutions. This was indicated by the systematic pH shift to higher values in the log S-pH curve in alkaline solution than expected from the Henderson-Hasselbalch equation. For pH < 3.9, saturated phosphate-containing saline solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt solubility products, intrinsic solubility, and complexation constants, which rationalized the data, were determined. Elemental, thermogravimetric (TGA), differential scanning calorimetric (DSC), and powder X-ray diffraction (PXRD) analyses were used to characterize the precipitates isolated from suspensions at different pH.This is the peer-reviewed version of the following article: Marković, O. S.; Pešić, M. P.; Shah, A. V.; Serajuddin, A. T. M.; Verbić, T. Ž.; Avdeef, A. Solubility-PH Profile of Desipramine Hydrochloride in Saline Phosphate Buffer: Enhanced Solubility Due to Drug-Buffer Aggregates. European Journal of Pharmaceutical Sciences 2019, 133, 264–274. [https://doi.org/10.1016/j.ejps.2019.03.014]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2926

The influence of competing counterions on the solubility of imipramine

Experimental studies of solubility are important in all phases of drug design and development. Solubility data are used to screen out drug-like candidates, biopharmaceutical classification and formulation optimization. The development of oral and parenteral dosage forms can be challenging, especially when drugs are poorly soluble, ionizable, exhibiting pH-dependent solubility and when multiple counterions are present in drug suspension. The influence of different counterions on the existing equilibria and on pH-dependent drug solubility must be defined in such systems. To investigate the effect of multiple ions on the solubility of a model basic drug – tricyclic antidepressant imipramine (Im), we conducted a systematic study of the Im solubility as a function of pH in the presence of both chloride and phosphate ions as well as in chloride-free and phosphate-free suspensions. The pH–Ramp shake–flask method1,2 was used for solubility determination. The computer program pDISOL–X was used for data analysis. It is shown that distinct pH-dependent solubility profiles were obtained in studied systems. Depending on the pH and the total concentration of chloride and/or phosphate ions, Im can precipitate as chloride and phosphate salt or free base. Furthermore, pH values of solid phase transitions (pHmax) varied as well. For instance, pHmax of solid phase transition of (ImH)H2PO4(s) to (ImH)2HPO4(s) change from 5.15 (chloride and phosphate-containing suspensions) to 5.73 (chloride-free suspensions). The intensive self-aggregation of Im in acidic region was suppressed by raising chloride or phosphate ions concentration (Iavg 1.42–1.64 M). In that way, solubility of Im was decreased due to the common-ion effect. This study illustrates the influence of competing counterions on Im solubility and on interconversions in solid phase. Hence, such factors must be taken into account during formulation optimization in drug research

The effect of methanesulfonic and glutaric acids on the solubility of clofazimine

In the modern drug research the number of practically insoluble potential drugs is increasing. Poor aqueous solubility can cause poor oral absorption and low bioavailability of drugs. Hence, solubility enhancement is considered as one of the most important challenges in the formulation and development of the dosage forms of drugs. Clofazimine (CFZ) is an antibiotic drug which is used in the treatment of tuberculosis and leprosy. It is recently shown that CFZ has inhibitory activity against certain coronaviruses and can antagonize the replication of SARS-CoV-2.1 Since CFZ is highly lipophilic molecule with extremely low solubility, it is quite a challenge to find appropriate method for CFZ solubilization. The aim of this work was to investigate the effect of methanesulfonic (MSA) and glutaric (GA) acids on the solubility of CFZ. The effect of MSA on the solubility of CFZ was studied by the pH-Ramp shake-flask method (pH-RSF).2 The solubility of CFZ was determined in the presence of GA in two ways: 1) by melting a mixture of CFZ and GA in different molar ratios, and then dissolving in water; 2) using the pH-RSF method. Interactions between CZ and GA were investigated by IR spectroscopy. It is shown that both MSA and GA increase the solubility of CFZ in acidic suspensions prepared by pH-RSF method. Also, solubility enhancement was observed in the molten CFZ-GA mixtures (molar ratio 1:1 and 1:4) compared to mixtures prepared without melting. Besides that, the IR spectra of these mixtures revealed that characteristic CFZ band was shifted in molted CFZ-GA mixture (molar ratio 1:1) probably due to CFZ-GA interactions. Preliminary results presented in this study illustrate that MSA and GA can be used for solubility improvement of CFZ