Risperidone/Randomly Methylated β-Cyclodextrin Inclusion Complex—Compatibility Study with Pharmaceutical Excipients

Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated β-cyclodextrin (RM-β-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-β-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.     

Application of thermal analysis in study of binary mixtures with metformin

Thermal analysis is an essential analytical tool in development of new formulations as well as to study the interaction between drugs and excipients. This work aims to investigate the possible interactions between metformin and excipients as microcrystalline cellulose (Microcel MC101®), starch sodium glycolate (Explosol®), sodium croscarmellose (Explosel®), PVP K30, magnesium stearate, starch and lactose, usually employed in pharmaceutical products. TG, DSC and DTA techniques were used for the thermal characterization to track if the thermal properties of the drug substance were modified in the mixture. Disregard of the starch and lactose systems, no changes in thermal behavior of mixtures were found. Thermogravimetric studies (TG) of metformin and its binary mixtures showed different thermal behavior.     

Thermal decomposition kinetics and compatibility studies of primaquine under isothermal and non-isothermal conditions

Primaquine (PQ) is the drug of choice for the radical cure of Plasmodium vivax malaria, and currently being administered in solid dosage form. In this study, the compatibility studies were carried out using differential scanning calorimetry (DSC), thermogravimetry (TG), and fourier transformed infrared (FT-IR). Non-isothermal and isothermal methods were employed to investigate kinetic parameters under nitrogen and air atmospheres using TG. The DSC investigations obtained by physical mixtures showed slight alterations in the melting temperatures of PQ with some excipients. The FT-IR confirmed the possible interactions obtained by DSC for the physical mixtures with PQ and lactose, magnesium stearate and mannitol. The results showed that the thermal decomposition followed a zero order kinetic in both atmospheres in non-isothermal method. The activation energy in both methods using nitrogen atmosphere was similar, and in air atmosphere the activation energy decreased.     

Compatibility studies between nebicapone,a novel COMT inhibitor,and excipients using stepwise isothermal high sensitivity DSC method

Study of excipients incompatibility with drugs in an early phase of pharmaceutical development is still a persistent difficulty within the pharmaceutical industry. We examine here the compatibility between an experimental drug (nebicapone) and common excipients using differential scanning calorimetry (DSC), high sensitivity DSC (HSDSC) and a conventional heat stress test. The results obtained indicate that nebicapone may be compatible with lactose monohydrate and sodium croscarmellose but is incompatible with magnesium stearate. This study concludes that HSDSC, in stepwise isothermal mode, may be used as a potential tool for detecting excipient incompatibilities.     

FTIR, XRD, and DSC analysis of the rosemary extract effect on polyethylene structure and biodegradability

The purpose of this research study was evaluation of the utility of two common multivariate techniques, agglomerative cluster analysis (CA) and principal component analysis (PCA), as supplementary means of detecting incompatibilities, which can occur between active pharmaceutical ingredients and excipients at the preformulation stage of a solid dosage form. For the detection of incompatibilities between atenolol (beta blocker) and selected excipients (mannitol, lactose, starch, methylcellulose, β-cyclodextrin, meglumine, chitosan, polyvinylpyrrolidone and magnesium stearate), the thermogravimetry (TG), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were chosen. The results have shown that compatibility between atenolol and an excipient can be identified in a CA dendrogram by two large clusters, from which one groups an excipient and physical mixtures with a high concentration of the excipient. Another cluster encompasses atenolol and mixtures with a high content of the drug. In the PCA plot, all samples are located along the first principal component axis (PC1), beginning from a single component located with the most negative PC1 value, through mixtures with gradually varying concentration of both ingredients, till the second component located close to the most positive PC1 values. The results have shown that CA and PCA fulfil their role as supporting techniques in the interpretation of the data acquired from the TG curves, and the obtained data are compatible with the results of DSC and FTIR analyses.     

Compatibility studies of trioxsalen with excipients by DSC,DTA, and FTIR

Psoralens are widely used for the treatment of psoriasis. Trioxsalen is a drug prescribed low-dose, belonging to the group of substituted psoralen. The aim of this study was to evaluate the compatibility of trioxsalen with pharmaceutical excipients used in the solid forms by analytical techniques. Binary mixtures between the trioxsalen and pharmaceutical excipients (namely, magnesium stearate, α-lactose, microcrystalline cellulose 102, pregelatinized starch, mannitol, sodium lauryl sulfate, sodium starch glycolate, and croscarmellose sodium) were examined. The trioxsalen–sodium lauryl sulfate mixture displayed some physical interaction based on the DTA and DSC results, but the FTIR study ruled out any chemical change.     

Pharmaceutical compatibility of dexamethasone with excipients commonly used in solid oral dosage forms

Dexamethasone is a glucocorticoid drug used for the treatment of acute and chronic inflammatory conditions, autoimmune diseases, some cancers, and several other pathologies. It is widely marketed worldwide especially under solid dosage forms. This study aimed to assess its compatibility with solid pharmaceutical excipients. Compatibility study was conducted through the preparation of binary mixtures (1:1, w/w) of dexamethasone with 12 selected excipients. Binary mixtures were analyzed by thermoanalytical techniques (thermogravimetric and differential thermal analysis), Fourier transform infrared spectroscopy, and X-ray diffraction. TG curves pointed only slight anticipations of dexamethasone decomposition. DTA curves showed interactions signs with microcrystalline cellulose 101 and 102, magnesium stearate, mannitol, and polyvinylpyrrolidone. Drug infrared absorption profile was not affected by the mixture with most excipients. X-ray diffractograms of all binary mixtures did not exhibit signs of interactions with changes of dexamethasone crystalline state. These results pointed that the interactions found by DTA technique were probably heat-induced. Therefore, the above-mentioned excipients should be carefully used in solid dosage forms with heat-based manufacturing processes.

     

Preformulation studies for atorvastatin calcium

This paper deals with the study of compatibility between antihyperlipidemic agent atorvastatin calcium trihydrate (ATV) and eight pharmaceutical excipients used in the development of solid dosage forms, namely citric acid, anhydrous lactose, magnesium citrate, magnesium carbonate, sodium carboxymethyl cellulose, polyvinylpyrrolidone K30, colloidal silica and sorbitol. As investigational tools, universal attenuated total reflectance Fourier transform infrared spectroscopy and powder X-ray diffractogram patterns were used for binary mixtures of ATV with each excipient at ambient condition and then completed by subjecting the samples to thermal stress using thermal analysis (TG/DTG/HF), in non-isothermal conditions and in oxidative medium. It was shown the binary mixtures do not present interactions between ATV and excipients when stored under ambient conditions for 2 months, while under thermal stress, ATV presents interactions with sorbitol.

     

Characterization and compatibility study of desloratadine

Desloratadine (DL) is a selective antagonist of the histamine H₁ receptor, which has been widely used to treat allergic symptoms, and stands out from other drugs in this therapeutic class because it does not cause sedative effects. In the present study, the physico-chemical properties of DL were fully characterized using six analytical techniques such as Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TG/DTG), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, Powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The DSC curve shows a sharp endothermic event at 158.4 °C, and the TG/DTG curve presents two decomposition events between 178.4 and 451.9 °C. A compatibility study involving DL and nine pharmaceutical excipients generally used in pharmaceutical formulations was performed. Physical binary mixtures of DL with each excipient were prepared in a 1:1 (w/w) ratio. After preparation, the samples were analyzed immediately and the results reveal solid-state interaction with anhydrous lactose, microcrystalline cellulose, magnesium stearate, and stearic acid.     

Physicochemical characterization of dipeptidyl peptidase-4 inhibitor alogliptin in physical mixtures with excipients

Alogliptin (ALG) is a hypoglycemic drug used in diabetes which inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), preventing the degradation of incretins, stimulating insulin secretion. The physicochemical characteristics of ALG were evaluated by differential scanning calorimetry (DSC), thermogravimetry (TG) and scanning electron microscopy equipped with energy-dispersive X-ray spectrometer (SEM/EDS). The compatibility studies were carried out between ALG and excipients (physical mixtures, 1:1) using DSC, TG, diffuse reflectance Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and hot-stage microscopy. ALG presented purity near to 99%, melted in the range of 179.4–187.2 °C, followed by decomposition which started in 198.0 °C. SEM/EMS analysis of ALG presented irregular crystals and traces of impurities as copper and lead. DSC investigations obtained by physical mixtures showed minor alterations in the melting ranges of ALG with mannitol, magnesium stearate and commercial tablets. Solubilization of ALG in the fused excipient was observed by hot-stage microscopy between mannitol and ALG, and in tablets. The interaction observed in the mixture with magnesium stearate is due to the melting of the excipient and drug separately, first the excipient and then the drug. FTIR showed additional bands related to the excipients. XRPD proved that ALG has a crystal form and no alterations in the ALG profile were observed after the mixtures. ALG was compatible with all excipients tested. These results were important to understand the characteristics, stability and compatibility of the drug, and proved to be useful in preformulation studies.

     

Compatibility study between indomethacin and excipients in their physical mixtures

Thermal analysis is a routine method for analysis of drugs and substances of pharmaceutical interest. Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) are thermoanalytical methods which offer important information about the physical and chemical properties of drugs (purity, stability, phase transition, polymorphism, compatibility, kinetic analysis, etc.). This work exemplifies a general method of studying the drug-excipient interactions with the aim of predicting rapidly and inexpensively the long thermal stability of their mixtures. The TG/DTG and DSC were used as screening techniques for assessing the compatibility between indomethacin (IND) and its physical associations as binary mixtures with some common excipients. Based on their frequent use in preformulations eleven different excipients: corn starch, microcrystalline cellulose (PH 101; PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinilpyrrolidone K30, magnesium stearate, talc, stearic acid, and manitol were blended with IND. The samples were prepared by mixing the analyte and excipients in a proportion of 1:1 (w:w). In order to investigate the possible interactions between the components, the thermal curves of IND and each selected excipient were compared with those of their 1:1 (w/w) physical mixtures. FT-IR spectroscopy and X-ray powder diffraction were used as complementary techniques to adequately implement and assist in interpretation of thermal results. On the basis of thermal results, confirmed by FT-IR and X-ray analyses, a possible interaction was found between IND with polyvinylpyrrolidone K30, magnesium stearate, and stearic acid.     

Compatibility study between chitosan and pharmaceutical excipients used in solid dosage forms

Microcrystalline cellulose is an excipient widely used in solid dosage forms as adsorbent, suspending agent, diluent, and disintegrant, depending on the percentage employed in the formulation. The structural similarity between cellulose and chitosan and the ecological advantage in the manufacturing process of chitosan have justified and reinforced the study of this polysaccharide as a novel pharmaceutical excipient. Nevertheless, it still does not appear to be present as constituent in any marketed medicine due to the absence of regulatory hurdles to standardize its physicochemical and functional specifications as well as its compatibility with other formulation ingredients. The physical compatibilities between chitosan and the most excipients used in solid dosage forms, such as diluents (microcrystalline cellulose, starch, lactose monohydrate, dicalcium phosphate dihydrate, and calcium carbonate), disintegrants (sodium starch glycolate, and croscarmellose sodium), and glidants (magnesium stearate, talc, sodium lauryl sulfate, and colloidal silicon dioxide), were studied by thermal analysis and FT-IR. In order to facilitate the IR spectra interpretations, an ad hoc algorithm was used to generate theoretical spectra to be compared with the respective experimental ones. Chitosan proved to be physically compatible with microcrystalline cellulose, starch, lactose, sodium starch glycolate, croscarmellose sodium, talc, colloidal silicon dioxide, and sodium lauryl sulfate. Moreover, chitosan raises the thermal stability of cellulose from 310 to 330 °C. Once the amino groups of chitosan were able to form coordination complexes with divalent cations of dicalcium phosphate dihydrate, calcium carbonate, and magnesium stearate, they were considered incompatible with chitosan.     

Evaluation of compatibility of tablet excipients and novel synthesized polymer with lamivudine

The present study describes compatibility of anti-HIV drug lamivudine with various selected excipients and a novel synthesized polymer, for the development of its controlled release formulation. Differential scanning calorimetry (DSC), isothermal stability study (ISS) and Fourier transform infrared (FT-IR) spectral analysis were performed to access the compatibility. The compatibility study was performed with various common excipients like spray dried lactose, polyvinyl pyrrolidine K-30, magnesium stearate, talc and a novel synthesized polymer cross-linked sago starch with lamivudine.     

DSC and physico-chemical properties of a substituted pyridoquinoline and its interaction study with excipients

The 4,6-bis[2′(diethylamino)ethoxy]2,8,10-trimethylpyrido[3,2-g]quinoline (BG 637) is one of the compound from the pyrido[3,2-g] quinolines family. This compound had in vitro activity against the resistant cells and can reverse the multidrug resistance developed during the chemotherapeutic treatments. To characterize BG 637, techniques such as differential scanning calorimetry (DSC), Fourier transform infrared spectrometer (FTIR), ultra violet spectrophotometry (UV), gas chromatography coupled with mass spectrometry (GC/MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction (XRPD) were used. Several of them were also used to show the stability of the drug during various storage conditions. DSC, FTIR and UV were used as screening techniques for assessing the compatibility of BG 637 with several commonly used pharmaceutical excipients. We compared the properties of the pure drug with those of binary mixture drug/excipient. Studied excipients were lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, sodium croscarmellose and magnesium stearate. Melting temperature and enthalpy of BG 637 in binary mixtures were similar to theoretical values. These results showed that BG 637 is a very stable compound and compatible with several pharmaceutical excipients.     

Study of stability and drug-excipient compatibility of diethylcarbamazine citrate

Diethylcarbamazine citrate (DEC) is the main drug used in the lymphatic filariasis treatment. This study aimed to evaluate drug-excipient compatibility of binary mixtures (BMs) (1:1, w/w), initially by differential scanning calorimetry (DSC), and subsequently, if there were any interaction evidence, by complementary techniques, such as thermogravimetric (TG), non-isothermal kinetics, Fourier transform infrared (FT-IR), and X-ray diffraction (XRD). For the analyses of the BMs by DSC, we selected those with Tabletose^®, representing the excipients containing lactose, polivinilpirrolidona (PVP), and magnesium stearate (MgS). The additional analyses by FT-IR and XRD showed no interaction evidence. The TG curves of DEC–Tabletose^® showed no signs of interaction, unlike the TG curves of PVP and MgS, confirming the results of non-isothermal kinetics, in which the BMs with PVP and MgS decreased the reaction activation energy. Thus, it was concluded after evaluation that the excipients, especially the PVP and MgS, should be avoided.     

Compatibility studies between captopril and pharmaceutical excipients used in tablets formulations

Captopril (CAP) was the first commercially available angiotensine-converting enzyme (ACE) inhibitor. In the anti-hypertensive therapy is considered the selected drug has to be therapeutically effective together with reduced toxicity. CAP is an antihypertensive drug currently being administered in tablet form. In order to investigate the possible interactions between CAP and excipients in tablets formulations, differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis completed by X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) were used for compatibility studies. A possible drug-excipient interaction was observed with magnesium stearate by DSC technique.     

Sibutramine hydrochloride monohydrate

In the present work, the thermal decomposition of sibutramine hydrochloride monohydrate (SBT) (an appetite suppressant agent) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Solid-state characterization was carried out by diffuse reflectance infrared fourier transform spectroscopy (DRIFT), scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Isothermal and non-isothermal methods were employed to determine the kinetic data of decomposition process. From isothermal experiments, activation energy (Ea) can be obtained from slope of ln t versus 1/T, and the value obtained was 96.06 and 101.43 kJ mol⁻¹ in N₂ and air atmospheres, respectively. For non-isothermal method Ea can be obtained from plot of logarithms of heating rates, as a function of inverse of temperature, resulting in a value of 96.56 and 98.22 kJ mol⁻¹ in N₂ and air atmospheres, respectively. The compatibilities of several commonly used pharmaceutical excipients (microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, lactose monohydrate) and empty hard-gelatin capsules with SBT were evaluated using DSC. The 1:1 physical mixtures of these excipients with SBT showed physical interaction of the drug with magnesium stearate. On the other hand, DRIFT results did not evidence any chemical modifications.     

Polymorphic transformation as a result of atovaquone incompatibility with selected excipients

Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy, and hot-stage microscopy were employed to evaluate the drug–excipient compatibility of atovaquone with commonly used tablet excipients. The DSC curves of pure drug and excipients were compared with their physical mixtures. Microcrystalline cellulose, titanium dioxide, colloidal silica, ferric oxide, lactose monohydrate, and sodium starch glycolate were compatible, while magnesium stearate, polyethylene glycol (PEG) 8000, Poloxamer 188, and hydroxypropyl methyl cellulose (HPMC) E15 showed incompatibility with the drug. Heat–cool–heat analysis of the physical and the ground mixture of later three excipients showed polymorphic transformation of atovaquone form III to form I, which occurred via amorphization with HPMC E15 and through solubilization mechanism with remaining two excipients. These outcomes were further supported by hot-stage microscopy. Results of milling experiments revealed a milling time-dependent polymorphic transformation and solubilization with HPMC E15 and PEG 8000, respectively. This study highlights the importance of compatibility assessment for selection of excipients in specific unit operations such as milling and grinding.     

Compatibility study between ibuprofen and excipients in their physical mixtures

The thermal techniques of analysis were used to assess the compatibility between ibuprofen (IB) and some excipients used in the development of extended released formulations. This study is a part of a systematic study undertaken to find and optimizes a general method of detecting the drug–excipient interactions, with the aim of predicting rapidly and assuring the long-term stability of pharmaceutical product and speeding up its marketing. The thermal properties of IB and its physical association as binary mixtures with some common excipients were evaluated by thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry. FT-IR spectroscopy and X-ray powder diffraction (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the thermal results. Based on their frequent use in preformulations nine different excipients: starch; microcrystalline cellulose (PH 101 and PH 102); colloidal silicon dioxide; lactose (monohydrate and anhydre); polyvinylpyrrolidone; magnesium stearate and talc were blended with IB. The samples were prepared by mixing the analyte and excipients in a proportion of 1:1 (w:w). The TG/DSC curves of the IB have shown a single stage of mass loss between 175 and 290 °C, respectively, an endothermic peak at 78.5 °C, which corresponds to the melting (literature T _m = 75–78 °C).