Lokesh Kumar

Trends in pharmaceutical taste masking technologies: a patent review

According to the year 2003 survey of pediatricians by the American Association of Pediatrics, unpleasant taste was the biggest barrier for completing treatment in pediatrics. The field of taste masking of active pharmaceutical ingredients (API) has been continuously evolving with varied technologies and new excipients. The article reviews the trends in taste masking technologies by studying the current state of the art patent database for the span of year 1997 to 2007. The worldwide database of European patent office (http://ep.espacenet.com) was employed to collect the patents and patent applications. It also discusses the possible reasons for the change of preferences in the taste masking technologies with time. The prime factors critical to the selection of an optimal taste masking technique such as the extent of drug bitterness, solubility, particle characteristics, dosage form and dose are briefly discussed.

Solid State Characterization of Commercial Crystalline and Amorphous Atorvastatin Calcium Samples

Atorvastatin calcium (ATC), an anti-lipid BCS class II drug, is marketed in crystalline and amorphous solid forms. The objective of this study was to perform solid state characterization of commercial crystalline and amorphous ATC drug samples available in the Indian market. Six samples each of crystalline and amorphous ATC were characterized using X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis, Karl Fisher titrimetry, microscopy (hot stage microscopy, scanning electron microscopy), contact angle, and intrinsic dissolution rate (IDR). All crystalline ATC samples were found to be stable form I, however one sample possessed polymorphic impurity, evidenced in XRPD and DSC analysis. Amongst the amorphous ATC samples, XRPD demonstrated five samples to be amorphous ‘form 27’, while, one matched amorphous ‘form 23’. Thermal behavior of amorphous ATC samples was compared to amorphous ATC generated by melt quenching in DSC. ATC was found to be an excellent glass former with Tg/Tm of 0.95. Residual crystallinity was detected in two of the amorphous samples by complementary use of conventional and modulated DSC techniques. The wettability and IDR of all amorphous samples was found to be higher than the crystalline samples. In conclusion, commercial ATC samples exhibited diverse solid state behavior that can impact the performance and stability of the dosage forms.

Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs

Polymorphism plays a critical role during pharmaceutical development, as it helps in the selection of optimal solid form. In present study, mechanical properties of ranitidine hydrochloride polymorphs were studied using instrumented tablet press, to understand the effect of crystal packing on the compaction behaviour. Out-of-die compressibility plot and Heckel analysis confirmed greater plastic deformation of form II over form I. Detailed crystallographic examination revealed that form I has several weak C–H⋯O interactions across the ‘proposed slip plane’ parallel to (−2 0 2) that prevent slip under compaction pressure. On the other hand, crystal structure of form II was relatively more open and multiple slip were possible under compaction pressure. These crystallographic features offered increased compressibility and deformability to form II. In absence of an active slip plane system, closed crystal structure of form I resists deformation under compaction pressure and hence showed poor compressibility and higher mean yield pressure. However, form I showed greater tabletability at a given compaction pressure, by virtue of its greater bonding strength.

Effect of counterions on the properties of amorphous atorvastatin salts

Amorphous systems have gained importance as a tool for addressing delivery challenges of poorly water soluble drugs. A careful assessment of thermodynamic and kinetic behavior of amorphous form is necessary for successful use of amorphous form in drug delivery. The present study was undertaken to evaluate effect of monovalent sodium (Na(+); ATV Na), and bivalent calcium (Ca(2+); ATV Ca) and magnesium (Mg(2+); ATV Mg) counterions on properties of amorphous salts of atorvastatin (ATV) model drug. Amorphous form was generated from crystalline salts of ATV by spray drying, and characterized for glass transition temperature (T(g)), fragility and devitrification tendency. In addition, chemical stability of the amorphous salt forms was evaluated. Fragility was studied by calculating activation enthalpy for structural relaxation at T(g), from heating rate dependency of T(g). Density functional theory and relative pK(a)s of counterions were evaluated to substantiate trend in glass transition temperature. T(g) of salts followed order: ATV Ca>ATV Mg>ATV Na. All salts were fragile to moderately fragile, with D value ranging between 9 and 16. Ease of devitrification followed the order: ATV Na∼ATV Mg≫ATV Ca, using isothermal crystallization and reduced crystallization temperature method. Chemical stability at 80°C showed higher degradation of amorphous ATV Ca (∼5%), while ATV Na and ATV Mg showed degradation of 1-2%. Overall, ATV Ca was better in terms of glass forming ability, higher T(g) and physical stability. The study has importance in selection of a suitable amorphous form, during early drug development phase.

NP-647, a novel TRH analogue: investigating physicochemical parameters critical for its oral and parenteral delivery.

NP-647 (L-pGlu-(2-propyl)-L-His-L-ProNH(2)) is a novel thyrotropin releasing hormone (TRH) analogue, with potential antiepileptic activity. In the present study, the physicochemical parameters of NP-647, including its solid state properties, dissociation constant, partition coefficient, solubility (intrinsic solubility and pH-solubility profile) and stability (gastrointestinal enzymatic stability, pH-stability profile and temperature stability) were investigated for their criticality for oral and parenteral delivery. NP-647 was characterized as amorphous material having glass transition temperature of 66.73 °C at 50% RH. It was found very hygroscopic with deliquescent in nature. pK(a) of the compound, as determined using potentiometric titration, was found to be 7.2 ± 0.02 (basic). Intrinsic solubility and pH-solubility behavior were determined using dissolution titration template method. NP-647 has intrinsic solubility of 2.4 ± 0.01 mg mL(-1). Partition/distribution studies indicate that NP-647 has a low log P (-1.07 ± 0.06) and log D(7.4) (-1.20 ± 0.02), characteristic of hydrophilic molecule. It was found most stable in tartrate buffer of pH of 5.0. Arrhenius plot of NP-647 suggest its half life of ∼ 3.2 years and shelf life of ∼ 6 months. These studies conclude that amorphous nature of NP-647 with deliquescent property will be critical in its solid oral dosage formulation and need to be investigated further.

Preparation and Characterization of Salt Forms of Enalapril

Selection of an optimal salt form of a drug candidate is a vital component of preformulation stage of drug development. In this study, six salts of enalapril – citrate, mesylate, tartrate, malate, besylate and tosylate – were prepared and characterized by Mass Spectroscopy, Differential Scanning Calorimetry, Thermogravimetric Analysis, Microscopy, Powder X-ray Diffraction, Karl Fischer Titration, High Performance Liquid Chromatography, Fourier-Transform Infra-red Spectroscopy and Head Space Gas Chromatography. All the six salts were subjected to a tiered screening involving five stages in the following order: crystallinity, hygroscopicity, solubility, stability and flow/compactability. Enalapril malate showed encouraging profile because of its lower hygroscopicity, higher solubility, good solid state stability, and better flow and compactability, in comparison to the marketed maleate salt.

Estimating relative stability of polymorphs by generation of configurational free energy phase diagram.

Relationship between two polymorphs is described to be either enantiotropic or monotropic with transition temperature/transition point (T(t) ) below the melting point (T(m) ) of the lower melting form in former case and above the T(m) of the higher melting form in latter case. In the present work, a new methodology for assessing thermodynamic T(t) of two polymorphs has been developed. Configurational free energy (G(c) ) of amorphous with respect to each polymorph was calculated to determine the T(t) . This method was used to determine the T(t) and polymorphic relationship of two model drugs, namely, carbamazepine and nateglinide. This method was also compared with the previous methodologies. Deduced T(t) of carbamazepine using this methodology was compared with previously reported values and was found to be in good agreement. A monotropic relationship was established between nateglinide polymorphs based on T(t) obtained by present methodology and previous reported methodologies.

Validated HPLC Method for Concurrent Determination of Antipyrine, Carbamazepine, Furosemide and Phenytoin and its Application in Assessment of Drug Permeability through Caco-2 Cell Monolayers

The present work explains the development and validation of a simple, rapid and sensitive liquid chromatographic method for the simultaneous determination of antipyrine (ANT), carbamazepine (CBZ), furosemide (FSD) and phenytoin (PHTN). Chromatographic analysis was carried out by a reversed phase technique on a C18 column, using water pH 3.0 and 50:50 mixtures of methanol and acetonitrile (58:42 v/v) as the mobile phase, at a flow-rate of 1.0 ml/min and a column temperature of 40°C. Detection was carried out at 205 nm for CBZ and PHTN and at 230 nm for ANT and FSD. The proposed method was evaluated for validation parameters including linearity, range, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ) and specificity. Elution of drugs ANT, FSD, PHTN, and CBZ was observed at 4.1, 5.1, 12.3 and 13.5 min, respectively. The method was found to be linear (R2 ≥ 0.999) in the concentration range of 5–100 μM, with an acceptable accuracy and relative standard deviation. Results of intra- and inter-day validation (n=3) showed the method to be efficient for routine determination of these permeability markers in Caco-2 cell monolayer permeability studies. The method was successfully utilized for determination of standard compounds in Caco-2 permeability experiments.

Investigation of the atypical glass transition and recrystallization behavior of amorphous prazosin salts.

This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ∼ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development.

Chapter 1 – Atorvastatin Calcium

Publisher Summary Atorvastatin calcium is used as an adjunct to diet to reduce the elevated total-cholesterol, low-density lipoprotein (LDL), apolipoprotein B (apo B), and triglyceride (TG) levels, and to increase the high-density lipoprotein cholesterol (HDL-C) level in patients with primary hypercholesterolemia and mixed dyslipidemia. The drug is also used for the treatment of patients with an elevated serum TG levels and for patients with primary dysbetaliproteinemia, who do not respond adequately to diet. Atorvastatin calcium is also indicated to reduce the total cholesterol and low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (e.g., LDL apheresis). Metabolism and pharmacokinetics of the drug Atorvastatin calcium is presented in this chapter. The absorption, distribution, metabolism, toxicity, and elimination (ADMTE) properties of the drug are discussed in this chapter. The chapter also discusses toxicity, such as muscle-related toxicity, gastrointestinal side effects, liver-related toxicity, and other side effects. Myotoxic side effects, including myopathy or rhabdomyolysis, have been observed with the usage of Atorvastatin calcium. Painful myalgia with a significant creatine kinase release (>2000 IU/l) is also associated with the use of Atorvastatin. Gastrointestinal side effects, such as constipation, flatulence, dyspepsia, and abdominal pain, are common with the consumption of the drug. Hepatic dysfunction due to Atorvastatin administration is characterized by a raised serum aspartate (AST) or alanine (ALT) level. Demyelinating neuropathies have been reported in some individuals.