Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid State, and Quality of 3D-Printed Dosage Forms.

This research study utilized a light-sensitive drug, nifedipine (NFD), to understand the impact of processing parameters and formulation composition on drug degradation, crystallinity, and quality attributes (dimensions, hardness, disintegration time) of selective laser sintering (SLS)-based three-dimensional (3D)-printed dosage forms. Visible lasers with a wavelength around 455 nm are one of the laser sources used for selective laser sintering (SLS) processes, and some drugs such as nifedipine tend to absorb radiation at varying intensities around this wavelength. This phenomenon may lead to chemical degradation and solid-state transformation, which was assessed for nifedipine in formulations with varying amounts of vinyl pyrrolidone-vinyl acetate copolymer (Kollidon VA 64) and potassium aluminum silicate-based pearlescent pigment (Candurin) processed under different SLS conditions in the presented work. After preliminary screening, Candurin, surface temperature (ST), and laser speed (LS) were identified as the significant independent variables. Further, using the identified independent variables, a 17-run, randomized, Box-Behnken design was developed to understand the correlation trends and quantify the impact on degradation (%), crystallinity, and quality attributes (dimensions, hardness, disintegration time) employing qualitative and quantitative analytical tools. The design of experiments (DoEs) and statistical analysis observed that LS and Candurin (wt %) had a strong negative correlation on drug degradation, hardness, and weight, whereas ST had a strong positive correlation with drug degradation, amorphous conversion, and hardness of the 3D-printed dosage form. From this study, it can be concluded that formulation and processing parameters have a critical impact on stability and performance; hence, these parameters should be evaluated and optimized before exposing light-sensitive drugs to the SLS processes.

Formulation, Optimization, and In vivo Evaluation of Gastroretentive Drug Delivery System of Nifedipine for the Treatment of Preeclampsia.

The study aimed to develop gastroretentive drug delivery system of nifedipine, its optimization, and in vivo evaluation. Bilayered tablet of nifedipine was prepared using central composite design with 3 factors, 5 responses, and 15 experimental trials. Response surface methodology along with numerical and graphical optimization was used to select the best formulation. Scanning electron microscopy study of optimized tablet at different time interval was carried out which showed formation of porous structure on the tablet surface. In vivo studies for optimized formulation were carried out on 10 healthy human volunteers and obtained pharmacokinetic parameters were compared with the marketed formulation, "Nicardia XL." Optimized formulation containing 3.083 mg HPMC K15M, 29.859 mg HPMC E15LV, and 3.541 mg Carbopol 974P releases the drug in a desired manner and remain buoyant for more than 12 h in human stomach. Both the formulations were found to have similar in vitro release profile (f1 4.5089 and f2 55.8274) and also were found to be bioequivalent. Finally, the stability study of the optimized formulation proved the integrity of the optimized formulation. Hence, the data suggest gastroretention as a promising approach to enhance bioavailability of nifedipine.

Preparation of nano-alkalinecellulose carboxylates (NACCs) as the methylene blue sorbent and as the catalyst for the large-scale nifedipine synthesis.

In this work, various new nano-alkalinecellulose carboxylates (NACCs) were prepared by oxidative hydrolysis of microalkalinecellulose (MACp) given from prewashed cotton. After the optimization of the reaction time, temperature, oxidant system, and oxidant loading, the new flake-shape anionic NACC24 with base capacity 10.8 mmol HO-/g was obtained from MACp at 50 °C. The characterized NACC24 and MACp were comparatively used as bio-sorbent for removal of methylene blue (MB) from wastewater and as the catalyst in the large-scale synthesis of nifedipine. With the Langmuir model and monolayer pseudo-second-order kinetic mechanism, the negatively charged polymer NACC24 represented high sorption capacity for the MB removal at 780 ±â€¯10 mg/g. A high regeneration stability and 90.5% original efficiency was verified for the NACC24 after five consequence adsorption-desorption cycles, where acidic methanol and aqueous NaOH were used for the efficient desorption of electrostatically interacted MB to NACC24 and respective reactivation of the NACC24 for further runs. Besides, NACC24 showed a high catalytic activity in the base-catalyzed rapid synthesis of anti-hypertension nifedipine even after the five times reusing of catalyst.

Synthesis and characterization of impurities of barnidipine hydrochloride, an antihypertensive drug substance.

Barnidipine hydrochloride is a long term dihydropyridine calcium channel blocker used for the treatment of hypertension. During the process development of barnidipine hydrochloride, four barnidipine impurities were detected by high-performance liquid chromatography (HPLC) with an ordinary column (Agilent ZORBAX Eclipse XDB-C18, 150 mm×4.6 mm, 5 µm). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, 1H-NMR, and 13C-NMR). The identification of these impurities should be useful for quality control in the manufacture of barnidipine.

Synthesis and biological evaluation of some novel 1,4-dihydropyridines as potential antitubercular agents.

Recent studies showed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have significant antitubercular activity. In this study, we have synthesized new derivatives of 1,4-dihydropyridines bearing carbmethoxy and carbethoxy group at C-3 and C-5 of the 1,4-dihydropyridine ring. In addition, 1H-pyrazole ring is substituted at C-4 position. These analogues were synthesized by multi-component Hantzsch reaction. The in vitro antitubercular activity of compounds against Mycobacterium tuberculosis H(37) Rv was evaluated. The lowest minimum inhibitory concentration value, 0.02 µg/mL and SI > 500, was found for dimethyl 1,4-dihydro-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethylpyridine-3,5-dicarboxylate 3f, diethyl 1,4-dihydro-4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethylpyridine-3,5-dicarboxylate 4c and diethyl 1,4-dihydro-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,6-dimethyl pyridine-3,5-dicarboxylate 4e, making them more potent than first-line antitubercular drug isoniazid. In addition, these compounds exhibited relatively low cytotoxicity.

Synthesis and evaluation of antioxidant, anti-inflammatory and antiulcer activity of conjugates of amino acids with nifedipine.

A new series of novel (2S)-2-({2-[1,4-dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridin-1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl) propanoic acid (3a) and its analogues 3b-j has been synthesized. These compounds were evaluated for their in vitro antioxidant activity, anti-inflammatory activity and antiulcer activity. Compounds 3b and f exhibited significant antioxidant action comparable with that of standard. Efficacy against inflammation and ulceration was also found to be significant. The chemical structures of these compounds were confirmed on the basis of spectral data.

Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.

The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.

Facile and efficient aromatization of 1,4-dihydropyridines with M(NO3)2.XH2O, TNCB, TBAP and HMTAI and preparation of deuterium labeled dehydronifedipine from nifedipine-d3.

The easy and efficient aromatization of various 1,4-dihydropyridines was investigated using various metal nitrates, trinitratocerium(IV) bromate (TNCB), and tetrabutyl ammonium periodate (TBAP) as oxidant in acetic acid at 100 degrees C, as well as hexamethylenetetramine-iodine (HMTAI) reflux in methanol. The efficient conversion of nifedipine-d(3) to dehydronifedipine-d(3) as an internal standard can be used in the measurement of nifedipine concentration in a body.

Design, synthesis, and calcium channel antagonist activity of new 1,4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent.

A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea pig ileal longitudinal smooth muscle. The results for the symmetrical ester series showed that increasing the length of the chain in C3- and C5-ester substituents increased the activity and the most active compound was the diphenylethyl ester derivative, so it was more active than the reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increasing lipophilic properties in the R substituent, increased the activity. The most active compounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active than nifedipine.

Characterization of nifedipine microparticles prepared by hot air coating technique.

In the present work, the Hot Air Coating (HAC) technique was used to prepare microparticulate systems containing nifedipine. Binary mixtures constituting of nifedipine and cetearyl alcohol (CA) in different proportions (30:70, 50:50, 70:30) were studied: they were homogenized by mixing or milling before spray treatment and successively subjected to a coating procedure with the HAC apparatus fed with air at 120 degrees C under a pressure of 4.5 atm. Morphology, entrapment efficiency, drug stability, thermal behaviour and the drug dissolution profile of HAC-treated and non-treated materials were examined and compared. The HAC products show the possession of physical and physico-chemical properties and dissolution behaviour different from those of the initial physical mixtures. The operative conditions employed in the spray process allow the obtaining of microparticles containing relevant percentages of the drug (at least up to 50%). Moreover, the experimental results give evidence that the milling pre-treatment of mixtures, unlike mixing, has significant effects on the properties of the lipid-coated microparticles.

[Bisbenzothieno[3,2-b: 2',3'-e]pyridines]. / Bisbenzothieno[3,2-b: 2',3'-e]pyridine.

Heating potassium 3-aminobenzo[b]thiophene-2-carboxylate (1) with ethyl propiolate or ethyl 3-ethoxyacrylate in acetic acid yielded the ethyl 2-(6,12-Dihydro-bis[1]benzothieno[3,2-b:2',3'-e]pyridin-6-yl)acetate (3) as main product and 1,4-dihydro-[1]benzothieno[3,2-b]-4-pyridone (2) as by-product. The dihydropyridine (DHP) 3 was dehydrogenated with ammonium cerium nitrate (CAN) to give the pyridine (Py) 4. The half wave potential E(1/2) = 1.64 V showed that 3 was much more stable against oxidizing agents than the reference compound nifedipine with E(1/2) = 1.15 V. Alkaline saponification of the acetic acid ester 4 did not yield the corresponding acetic acid, because decarboxylation took place to form the methylpyridine 5.

[Pyrano[3,4-c]quinolines from 1-desaza--oxa-nifedipine]. / Pyrano[3,4-c]chinoline aus 1-Desaza-1-oxa-nifedipin.

Pyrano[3,4-c]quinolines from 1-desaza-1-oxa-nifedipine The reaction of the 1,5-diketone 1 with acetic anhydride/acetic acid in the presence of zinc chloride yields the 1-desaza-1-oxa-nifedipine 2 and the annulated lactone 3 as a by-product. The structures of 2 and 3 are confirmed by X-ray structure analysis. The pH-dependent reduction of the nitro group from 2 leads to the pyrano[3,4-c]quinolines 4Aa, b by ring closure. The cyclic hydroxamic acid 4Aa represents a weak, non-selective inhibitor of 5-, 12- and 15-lipoxygenase of human full-blood.

Synthesis and calcium channel blocker activity of alkyl 1,4-dihydro-2,6-dimethyl-4-nitrobenzyl thioimidazolyl-3,5-pyridinedicarboxylates.

New alkyl ester analogues of nifedipine, in which the orthonitrophenyl group of position 4 is replaced by 1-methyl 2-(p-nitrobenzyl)thio-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylen chain in C3 and C5 ester substituents decreased activity. When the presence of bulky lipophilic esters increased activity. In unsymmetrical diester series, the results showed when R1 is a small substituent (R1 = Me), increasing of the lipophilic property in R2 substituent increased the activity if this high lipophilicity don't accompany with steric hinderance. Our results demonstrate that the most active compound was diphenyl ester derivative and it was almost seven times more active than the reference drug nifedipine.

Decoration of dihydropyrimidine and dihydropyridine scaffolds with sugars via Biginelli and Hantzsch multicomponent reactions: an efficient entry to a collection of artificial nucleosides.

Here we present an overview of our work on the glycosylation of biologically relevant heterocycles. An array of stereochemically pure C-glycosylated dihydropyrimidine and dihydropyridine derivatives (artificial nucleosides) has been prepared. Our strategy involved the synthesis of suitably designed C-glycosylated reagents and their use as components in Biginelli and Hantzsch cyclocondensations. Molecular diversity has been explored within the collection on the basis of the nature and the number of sugar residues as well as their positions in the heterocyclic rings.

Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity.

We have synthesized a novel series of 18 dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates from anacardic acid, a natural compound found in cashew nut shells, and investigated their blocking action on L- and T-type calcium channels transiently expressed in tSA-201 cells. The IC(50) values for L-type calcium channel block obtained with the series ranged from 1 to approximately 40 microM, with higher affinities being favored by increasing the size of the alkoxy group on the 4-phenyl ring and ester substituent in the 3,5 positions. A detailed analysis of the strongest L-type channel blocker of the series (PPK-12) revealed that block was poorly reversible and mediated an apparent speeding of the time course of inactivation. Moreover, in the presence of PPK-12, the midpoint of the steady state inactivation curve was shifted by 20 mV toward more hyperpolarized potentials, resulting in an increase in blocking efficacy at more depolarized holding potentials. Surprisingly, PPK-12 blocked T- and L-type calcium channels with similar affinities. One of the weakest L-type channel inhibitors (PPK-5) exhibited a T-type channel affinity that was similar to that seen with PPK-12, resulting in a 40-fold selectivity of PPK-5 for T- over L-type channels. Thus, dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates may serve as excellent candidates for the development of T-type calcium-channel specific blockers.

[Strategies for the synthesis of nifedipine analog esters of l-ascorbic acid]. / Strategien zur Synthese Nifedipin-analoger Ester von L-Ascorbinsäure.

The synthesis of L-ascorbyl 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates was not successful using various modifications. The strategies are shown and 7 new L-ascorbic acid derivatives are synthesized, including the dispiro compound 14.

[Five-ring analogs of nifedipine. 3. Synthesis and reactions of 1,4-dihydropyridines with 4-(4-nitro-5-imidazolyl)-substituents]. / Fünfring-Analoga von Nifedipin 3. Mitt.: Darstellung und Reaktionen von 1,4-Dihydropyridinen mit 4-(4-Nitro-5-imidazolyl)-Substituenten.

In the Hantzsch pyridine synthesis the 4-nitro-5-imidazolylcarbaldehydes 4 react with methyl 3-aminocrotonate or 3-aminocrotononitrile in acetic acid to yield the 1,4-dihydropyridines (DHP) 5 and 6. The corresponding pyridines 7 and 8 are obtained by oxidation with cerium(IV) or chromium(VI), respectively. Reduction of the nitro group in 7 with iron in acetic acid leads to the lactames 9, while from 8a the imidazolylamine 10 is isolated. Compound 8a reacts with dithionite to yield the cyclic amidine 11. Irradiation of the DHP 5 and 6b with UV-A light affords the 4-nitroso-5-imidazolyl-pyridines 12 and 13. The half wave potentials E1/2 of the DHP 5 were determined by anodic oxidation using difference pulse voltammetry (DPV); nifedipine was used as reference substance. The DHP 5 inhibit the growth of Staphylococcus aureus in the platelet diffusion test.

Syntheses and calcium channel antagonist activity of nifedipine analogues with methylsulfonylimidazolyl substituent.

Various diester analogues of nifedipine in which the ortho nitrophenyl group at position 4 is replaced by 1-methyl-2-methylsulfonyl-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as a standard. Compound 6n was found to be the most active.

Synthesis and biological activity of two new calcium-channel blockers, mebudipine and dibudipine.

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mM)-treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.

Studies on nilvadipine. IV. Synthesis of deuteriated and optically active isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4- dihydropyridine-5-carboxylate (nilvadipine).

Nilvadipine, I, has already entered clinical use for the treatment of hypertension. In the process of the developing nilvadipine, we prepared the deuteriated analogue of I as an internal standard for the determination of I in human plasma by capillary column gas chromatography-negative-ion chemical-ionization mass spectrometer. Nilvadipine has an asymmetric center at the C-4 position of the dihydropyridine ring, and characterization of the optical isomers with regard to their activity and bioavailability is of interest. Thus, we synthesized both the enantiomers of I by optical resolution via the 5-carboxy derivative (3), which was previously prepared as one of the metabolites of I.