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.

     

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 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).     

Application of thermal analysis to the study of antituberculosis drugs–excipient compatibility

First-line drugs (rifampicin, RIF; isoniazid, INH; ethambutol, ETA; and pyrazinamide, PZA) recommended in conventional treatment of tuberculosis were analyzed in 1:1 w/w binary mixtures with microcrystalline cellulose MC 101 (CEL) and lactose supertab^® (LAC) by differential scanning calorimetry (DSC), thermogravimetry (TG), differential thermal analysis (DTA), and Fourier transformed infrared analysis (FTIR) as part of development of fixed dose combination (FDC) tablets. Evidence of interaction between drug and pharmaceutical excipients was supposed when peaks disappearance or shifting were observed on DTA and DSC curves, as well as decreasing of decomposition temperature onset and TG profiles, comparing to pure species data submitted to the same conditions. LAC was showed to interact with RIF (absence of drug fusion and recrystallization events on DSC/DTA curves); INH (thermal events of the mixtures different from those observed for drug and excipient pure in DSC/DTA curves); PZA (decrease on drug fusion peak in DSC/DTA curves), and ETA (shift on drug onset fusion and absence of pure LAC events on DSC/DTA curves). In all cases, an important decrease on the temperature of drug decomposition was verified for the mixtures (TG analysis). However, FTIR analysis showed good correlation between theoretical and experimental drug-LAC spectra except for INH–LAC mixture, evidencing high incompatibility between these two species and suggesting that those interactions with PZA and RIF were thermally induced. No evidence of incompatibilities in CEL mixtures was observed to any of the four-studied drugs.     

DSC Screening of Potential Prochlorperazine-Excipient Interactions in Preformulation Studies

Differential scanning calorimetry was used to examine the thermal behaviour of mixtures of the drug prochlorperazine with standard excipients, to assess potential interactions, and of mixtures with cyclodextrins, to investigate inclusion complexation which could increase the photostability of the drug. For most of the excipients (magnesium stearate, stearic acid, Explotab^®, Ac-Di-Sol^®, Encompress^® and Ludipress^®, lactose and Starch 1500) disappearance or broadening of the melting endotherm of the drug indicated interactions. Lubritab^® was the only 'inert' excipient tested. Mixtures of prochlorperazine and the cyclodextrins gave incomplete inclusion complexation as shown by only partial disappearance of the melting endotherm of the drug.     

Thermotropic phase behaviour of mixed liposomes of archaeal diether and conventional diester lipids

During preformulation studies of pharmaceutical solid dosage forms, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the drug and adjuvants of interest that might interfere with efficacy and safety of the final drug product. Differential scanning calorimetry (DSC) and thermogravimetry (TG) are useful tools for this purpose. The aim of this study was to investigate the thermoanalytical behavior of olanzapine (OLZ) when mixed with several excipients commonly used in solid dosage forms such as microcrystalline cellulose, croscarmellose, dicalcium phosphate dihydrate (DCPD), lactose, magnesium stearate, and povidone. Following DSC and TG analyses, powder X-ray diffraction tests were carried out. Thermoanalytical methods showed evidence of interaction between OLZ and magnesium stearate, lactose, and povidone. These results can be useful during the selection of excipients for pharmaceutical formulation development.     

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.     

Thermal behaviour, compatibility study and decomposition kinetics of glimepiride under isothermal and non-isothermal conditions

In the present work, the thermal decomposition of glimepiride (sulfonylurea hypoglycemic agent) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Isothermal and non-isothermal methods were employed to determine kinetic data of decomposition process. The physical chemical properties and compatibilities of several commonly used pharmaceutical excipients (glycolate starch, microcrystalline cellulose, stearate, lactose and Plasdone®) with glimepiride were evaluated using thermoanalytical methods. The 1:1 physical mixtures of these excipients with glimepiride showed physical interaction of the drug with Mg stearate, lactose and Plasdone®. On the other hand, IR results did not evidence any chemical modifications. From isothermal experiments, activation energy (E _a) can be obtained from slope of lnt vs. 1/T at a constant conversion level. The average value of this energy was 123 kJ mol^–1. For non-isothermal method E _a can be obtained from plot of logarithms of heating rates, as a function of inverse of temperature, resulting a value of 157 and 150 kJ mol^–1, respectively, in air and N₂ atmosphere, from the first stage of thermal decomposition.     

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.     

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.     

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 and Stability Studies of Propranolol Hydrochloride Binary Mixtures and Tablets for TG and DSC-photovisual

This study demonstrates the thermalanalysis applications in compatibility and stability studies of the propranolol binary mixture sand tablets A and B. The propranolol binary mixtures were prepared in the laboratory and compared to the fully formulated tablets using the thermogravimetric (TG) and calorimetric(DSC) methods. DSC of binary mixtures showed similar phase transition to propranolol drug. The tablets phase transition decreased and there was no detectable significant interaction in propranolol–lactose mixture and tablets. The DSC-photovisual test revealed an interaction similar to the Maillard reaction. The TG isothermal study showed a difference in the profile between the drug and tablets due excipients quality and problems in manufacture process. The kinetic parameters indicated a lower stability for the tablets than propranolol drug. The thermal techniques thermally differentiated the propranolol preparations demonstrating the importance in the design development of pharmaceuticals solid-dosage form. This revised version was published online in July 2006 with corrections to the Cover Date.     

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.     

Thermal studies of pre-formulates of metronidazole obtained by spray drying technique

Compatibility studies between active drugs and excipients are substantial in the pharmaceutical technology. The objective of the present work was to develop pre-formulated mixtures of metronidazole (MT) obtained by spray drying (SPDR) and their thermoanalytical characterization. Dynamic and isothermal TG, conventional DSC and DSC coupled to a photovisual system were used. DSC experiments with both techniques confirmed the homogeneity of the conventional and pre-formulated mixtures. The TG data made possible the comparison the thermal stability of the different mixtures. Similar thermal stabilities were found of the conventional and pre-formulated mixtures, with slower particles sizes of MT.     

Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV

The evaluation of sildenafil citrate (SC), the best-selling drug for treatment of impotence, for compatibility with various excipients was investigated using thermal and isothermal stress testing. Differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and liquid chromatography (LC) with ultraviolet detection were successfully employed to investigate the compatibility between SC and various excipients commonly used in solid form in the pharmaceutical industry. The studies were performed using 1:1 (m/m) drug/excipient physical mixtures and samples were stored under accelerated stability conditions (40 °C at 75% relative humidity). All excipients tested (such as colloidal silicon dioxide, croscarmellose sodium, lactose, mannitol and sucrose) showed potential incompatibilities by DSC and LC analysis after accelerated stability testing. However, some incompatibilities were not detected by the DSC method and were observed only when LC analysis was performed. HSM was able to differentiate active pharmaceutical ingredient degradation from solubilisation, supporting the interpretation of DSC in excipients where thermal events either overlapped or disappeared. The combination of both the analytical techniques (DSC and LC) and use of a stability chamber is extremely helpful in detecting incompatibilities and providing more robust and accurate approaches for pre-formulation studies.     

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.     

Thermal analysis and compatibility studies of prednicarbate with excipients used in semi solid pharmaceutical form

Differential Scanning Calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG) and infrared spectroscopy (IR) techniques were used to investigate the compatibility between prednicarbate and several excipients commonly used in semi solid pharmaceutical form. The thermoanalytical studies of 1:1 (m/m) drug/excipient physical mixtures showed that the beginning of the first thermal decomposition stage of the prednicarbate (T _onset value) was decreased in the presence of stearyl alcohol and glyceryl stearate compared to the drug alone. For the binary mixture of drug/sodium pirrolidone carboxilate the first thermal decomposition stage was not changed, however the DTG peak temperature (T _{peak DTG}) decreased. The comparison of the IR spectra of the drug, the physical mixtures and of the thermally treated samples confirmed the thermal decomposition of prednicarbate. By the comparison of the thermal profiles of 1:1 prednicarbate:excipients mixtures (methylparaben, propylparaben, carbomer 940, acrylate crosspolymer, lactic acid, light liquid paraffin, isopropyl palmitate, myristyl lactate and cetyl alcohol) no interaction was observed.     

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.     

Comparison of Generic Hydrochlorothiazide Formulations by Means of TG and DSC Coupled to a Photovisual System

The compatibilities and stabilities of some binary mixtures and generic hydrochlorothiazide formulations were studied by using TG, DSC and a DSC-photovisual system. The kinetic parameters were determined via the Arrhenius equations. Tablet B presented higher compatibility and thermal stability than those of tablets A and C. The photovisual system demonstrated that the decomposition of tablet A occurs before the melting point, due to the Maillard reaction between the hydrochlorothiazide and lactose present in the formulation. The behaviour and rate constants of binary mixtures suggest that lactose can be substituted for microcrystalline cellulose, MC(101), in tablet A. The DSC and TG data revealed different characteristics of compatibility and stability in generic formulations from different manufacturers. This revised version was published online in July 2006 with corrections to the Cover Date.     

Development of a sustained-release matrix tablet formulation of DHEA as ternary complex with α-cyclodextrin and glycine

Sustained-release matrix-tablets of dehydroepiandrosterone (DHEA) as ternary complex with α-cyclodextrin and glycine (c-DHEA) were prepared by direct compression with suitable excipients. The influence of the swelling properties of hydroxypropylmethylcellulose (HPMC) and the disintegrating power of Explotab^® used in combination, as well as the effect of the presence, type and amount of suitable channelling agents (Emcocel^® and spray-dried lactose, alone or in combination) on drug release behaviour from matrix-tablets has been evaluated. The best performances in terms of drug release was obtained from formulations containing a 75:25 w/w spray-dried lactose:Emcocel^® combination in the presence of HPMC as matrix-forming polymer, leading to a more than 65% DHEA released at the end of the test, a value which was, respectively, 1.9 and 2.7 times higher than those achieved with the corresponding formulations containing spray-dried lactose or Emcocel^® alone. The drug release profile from the most effective matrix-tablet formulation of c-DHEA allowed achievement of a more than 6-fold increase in the drug amount released within 24 h in comparison with the same formulation containing the simple physical mixtures of DHEA, α-cyclodextrin and glycine. Therefore the advantage of using DHEA as ternary complex, prepared by mechano-chemical treatment, was clearly demonstrated, thus allowing the development of an effective sustained-release formulation of the drug.