Abstract:
:Simvastatin is one of the most widely used active pharmaceutical ingredients for the treatment of hyperlipidemias. Because the compound is employed as a solid in drug formulations, particular attention should be given to the characterization of different polymorphs, their stability domains, and the nature of the phase transitions that relate them. In this work, the phase transitions delimiting the stability domains of three previously reported simvastatin forms were investigated from structural, energetics, and dynamical points of view based on single crystal X-ray diffraction (SCXRD), hot stage microscopy (HSM), and differential scanning calorimetry (DSC) experiments (conventional scans and heat capacity measurements), complemented with molecular dynamics (MD) simulations. Previous assignments of the crystal forms were confirmed by SCXRD: forms I and II were found to be orthorhombic ( P212121, Z'/ Z = 1/4) and form III was monoclinic ( P21, Z'/ Z = 2/4). The obtained results further indicated that (i) the transitions between different forms are observed at 235.9 ± 0.1 K (form III → form II) and at 275.2 ± 0.2 K (form II → form I) in DSC runs carried out at 10 K min-1 and close to these values when other types of techniques are used (e.g., HSM). (ii) They are enantiotropic (i.e., there is a transition temperature relating the two phases before fusion at which the stability order is reversed), fast, reversible, with very little hysteresis between heating and cooling modes, and occur under single crystal to single crystal conditions. (iii) A nucleation and growth mechanism seems to be followed since HSM experiments on single crystals evidenced the propagation of an interface, accompanied by a change of birefringence and crystal contraction or expansion (more subtle in the case of form III → form II), when the phase transitions are triggered. (iv) Consistent with the reversible and small hysteresis nature of the phase transitions, the SCXRD results indicated that the molecular packing is very similar in all forms and the main structural differences are associated with conformational changes of the "ester tail". (v) The MD simulations further suggested that the tail is essentially "frozen" in two conformations below the III → II transition temperature, becomes progressively less hindered throughout the stability domain of form II, and acquires a large conformational freedom above the II → I transition. Finally, the fact that these transitions were found to be fast and reversible suggests that polymorphism is unlikely to be a problem for pharmaceutical formulations employing crystalline simvastatin because, if present, the III and II forms will readily convert to form I at ambient temperature.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Simões RG,Bernardes CES,Joseph A,M Piedade MF,Kraus W,Emmerling F,Diogo HP,Minas da Piedade MEdoi
10.1021/acs.molpharmaceut.8b00818subject
Has Abstractpub_date
2018-11-05 00:00:00pages
5349-5360issue
11eissn
1543-8384issn
1543-8392journal_volume
15pub_type
杂志文章abstract::Penetratin is a classical cell-penetrating peptide with the potential to assist in the transmembrane delivery of proteins or drugs. However, the synthesis and application of cholesterol-penetratin (Chol-P) conjugates as nonviral delivery systems for microRNAs or drugs have not previously been reported. In this study, ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00211
更新日期:2016-07-05 00:00:00
abstract::Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has als...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00474
更新日期:2021-02-01 00:00:00
abstract::Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00466
更新日期:2018-08-06 00:00:00
abstract::Influenza viruses cause seasonal epidemics and represent a pandemic risk. With current vaccine methods struggling to protect populations against emerging strains, there is a demand for a next-generation flu vaccine capable of providing broad protection. Recombinant biotechnology, combined with nanomedicine techniques,...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00383
更新日期:2021-02-01 00:00:00
abstract::Nonviral transfections of six low passage human colon cancer cell lines using the artificial beta-catenin/TCF-dependent promoter CTP4 demonstrated a high promoter activity which was 1000- to 70000-fold higher than in HeLa control cells. Luciferase gene expression levels obtained with CTP4 in epithelial-like tumor cell...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp0600586
更新日期:2007-01-01 00:00:00
abstract::Viral nanotechnology is an emerging and highly interdisciplinary field in which viral nanoparticles (VNPs) are applied in diverse areas such as electronics, energy and next-generation medical devices. VNPs have been developed as candidates for novel materials, and are often described as "programmable" because they can...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp100225y
更新日期:2011-02-07 00:00:00
abstract::We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00562
更新日期:2020-10-05 00:00:00
abstract::Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain-blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can d...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00051
更新日期:2016-05-02 00:00:00
abstract::Gold nanoparticles (AuNPs) have a number of physical properties that make them appealing for medical applications. For example, the attenuation of X-rays by gold nanoparticles has led to their use in computed tomography imaging and as adjuvants for radiotherapy. AuNPs have numerous other applications in imaging, thera...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp3005885
更新日期:2013-03-04 00:00:00
abstract::Some of the most significant therapeutic leads and agents used for the treatment of cancer target microtubule dynamics. Paclitaxel is an exceptional example that is currently used for treating a wide range of tumors. New, non-taxane microtubule stabilizers, including several epothilones, are advancing through clinical...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp060016h
更新日期:2006-07-01 00:00:00
abstract::The effective delivery of bioimaging probes to a selected cancerous tissue has extensive significance for biological studies and clinical investigations. Herein, the peptide functionalized NaGdF4 nanodots (termed as, pPeptide-NaGdF4 nanodots) have been prepared for highly efficient magnetic resonance imaging (MRI) of ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00361
更新日期:2017-09-05 00:00:00
abstract::The development of cancer and fibrotic diseases has been shown to be highly dependent on disregulation of cap-dependent translation. Binding protein eIF4E to N(7)-methylated guanosine capped mRNA has been found to be the rate-limiting step governing translation initiation, and therefore represents an attractive target...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300699d
更新日期:2013-02-04 00:00:00
abstract::A combination of microbubbles (MBs) and ultrasound (US) is an emerging method for noninvasive and targeted enhancement of anti-cancer drug uptake. This method showed an increase local drug extravasation in tumor tissue while reducing the systemic adverse effects in various tumor models. The present study aims to evalu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00416
更新日期:2019-09-03 00:00:00
abstract::Dry powder inhalations (DPI) of microparticles containing isoniazid (INH) and rifabutin (RFB) are under preclinical development for use in pulmonary tuberculosis. Microparticles containing 0.25, 2.5, or 25 mg of each drug were administered daily for 90 days to rhesus macaques (n = 4/group). Single inhalations or intra...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300043f
更新日期:2012-04-02 00:00:00
abstract::The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal per...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp800088f
更新日期:2009-01-01 00:00:00
abstract::The impact of OATP drug uptake transporters in drug-drug interactions (DDIs) is increasingly recognized. OATP1B1 and OATP1B3 are human hepatic uptake transporters that can mediate liver uptake of a wide variety of drugs. Recently, we generated transgenic mice with liver-specific expression of human OATP1B1 or OATP1B3 ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00453
更新日期:2015-12-07 00:00:00
abstract::The tendency of highly supersaturated solutions of poorly water-soluble drugs to undergo liquid-liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds the amorphous solubility, for example, during dissolution of some amorphous solid dispersions, is thought to be advantageous...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01117
更新日期:2019-01-07 00:00:00
abstract::The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nano...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00737
更新日期:2017-12-04 00:00:00
abstract::Photostability conditions as prescribed by ICH guidelines induced highly reduction-resistant scrambled disulfides that contribute to the population of apparent nonreducible aggregates in an IgG1 mAb. Photoinduced cross-linked species were isolated under reducing conditions using an organic phase size exclusion chromat...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b01128
更新日期:2018-04-02 00:00:00
abstract::Intra-articular (IA) injection of thermoresponsive hydrogels coupled with microparticles (MPs) possess the benefit of sustaining the anti-inflammatory drug effect within the joint cavity for rheumatoid arthritis treatment. Star-shaped thermoresponsive poly(polyethylene glycol) methacrylate [Poly(PEGMA)] copolymers wer...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00126
更新日期:2020-06-01 00:00:00
abstract::Amphotericin B (AmB) is a lifesaving polyene antibiotic used widely to treat deep-seated mycoses. Both the pharmaceutical effectiveness as well as toxic side effects depend on molecular organization of the drug. In the present study, we analyzed steady-state fluorescence, fluorescence anisotropy spectra, fluorescence ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300143n
更新日期:2012-05-07 00:00:00
abstract::Interactions of a lyophilized peptide with water and excipients in a solid matrix were explored using photolytic labeling. A model peptide "KLQ" (Ac-QELHKLQ-NHCH3) was covalently labeled with NHS-diazirine (succinimidyl 4,4'-azipentanoate), and the labeled peptide (KLQ-SDA) was formulated and exposed to UV light in bo...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01031
更新日期:2019-03-04 00:00:00
abstract::In this study, the dissolution properties of celecoxib (CX) solid dispersions manufactured from Eudragit 4155F and polyvinylpyrrolidone (PVP) were evaluated. Hot-melt extrusion (HME) technology was used to prepare amorphous solid dispersions of drug/polymer binary systems at different mass ratios. The drug concentrati...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200157b
更新日期:2011-08-01 00:00:00
abstract::Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500586p
更新日期:2015-08-03 00:00:00
abstract::Iron oxide nanoparticles have great potential as diagnostic and therapeutic agents in cancer and other diseases; however, biological aggregation severely limits their function in vivo. Aggregates can cause poor biodistribution, reduced heating capability, and can confound their visualization and quantification by magn...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00866
更新日期:2016-07-05 00:00:00
abstract::In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic agents against brain metastases is limited by their inability to pe...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b01167
更新日期:2020-02-03 00:00:00
abstract::The molecular mechanisms of autophagy in polyethylenimine (PEI)-treated cells are not well understood because of the use of nonspecific autophagy inhibitors. Here, we applied autophagy-related gene expression analysis to pinpoint the molecular mechanisms of autophagy in PEI-treated wild-type and atg5 gene knockout (at...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500111u
更新日期:2014-09-02 00:00:00
abstract::Stereoregularity of polymers is known to influence their physicochemical and functional properties in the bulk form. Recent studies have also provided evidence for the effect of polymer stereoregularity on the physicochemical and functional properties of their self-assembled nanostructures. Research in this area has w...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01169
更新日期:2017-08-07 00:00:00
abstract::Paracetamol has been one of the most commonly used and prescribed analgesic drugs for more than a hundred years. Despite being generally well tolerated, it can result in high liver toxicity when administered in specific conditions, such as overdose, or in vulnerable individuals. We have synthesized and characterized a...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00508
更新日期:2019-10-07 00:00:00
abstract::To predict the outcome of intestinal drug transporter induction on pharmacokinetics, signaling of the DNA message along with messenger RNA (mRNA) transcription and protein translation leading to transporter function must be understood. We quantified the gene expression of PXR and CAR, gene expression and protein abund...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00458
更新日期:2019-09-03 00:00:00