Effect Of Formulation Factors Research Articles

Fabrication of gastro-floating sustained-release etoricoxib and famotidine tablets: design, optimization, in-vitro, and in-vivo evaluation

In this study, a new gastro-floating sustained-release tablet (GFT) with a combination of Etoricoxib (ET) and Famotidine (FM) was successfully developed. GFTs were prepared by using a combination of hydrophilic swellable natural/semi-synthetic polymers as a controlled-release layer. Through a 24 full factorial statistical experimental design, the effects of formulation factors on the release of GFTs were conducted. The ideal floating tablet (FT) comprised konjac-gum (150 mg), guar-gum (26.57 mg), xanthan-gum (54.17 mg), and HPMC-K15-M (69.25 mg). The ideal FT exhibited a high swelling index (SI) (297.7%) and rapid FLT (around 50 s) in 0.1 N HCl as well as controlled release of ET (22.43% in 1 h and 77.47% in 8 h) and FM (24.89% in 1 h and 93.82% in 8 h) with the absence of any drug-excipient interactions. The AUC0∼72 (ng h/mL) of ET and FM in the GFTs were approximately double-fold of the market, respectively. The relative bioavailability was (207.48 ± 12.02% and 208.51 ± 13.11%) compared with commercial tablets. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. These findings revealed the successful preparation of the sustained-release floating tablet with improved dual drug delivery.

Preparation and optimization of glyceryl monooleate-low molecular weight chitosan nanoparticles for delivery of morpholinopyrrolizine derivative

Purpose: To develop and optimize glyceryl monooleate–low-molecular-weight chitosan (GMO-LMWC) nanoparticles loaded with morpholinopyrrolizine derivative (NPM).
 Methods: Molecular mechanics was used to determine the main driving force for the complexation between glyceryl monooleate (GMO) and chitosan. Nanoparticles were fabricated using a modified film-rehydration method. Optimization was carried out using a statistical design approach. The effects of formulation factors (concentrations of GMO, LMWC and Tween 80) on zeta potential and particle size were investigated using a 23 factorial design.
 Results: A steady increase in binding energy was observed when chitosan length was increased from 22 to 142 Å, and thereafter it remained almost constant. The examined independent variables had significant effects on particle size and zeta potential. The particle size of the nanoparticles varied from 265 to 1270 nm while zeta potential was in the range of 3 – 12 mV. The optimized preparation showed a significantly low half-maximal inhibitory concentration (IC50) when compared to a free anticancer agent in the hepatocellular carcinoma (HePG-2) cell line.
 Conclusion: A nanoparticulate system composed of GMO and LMWC is a potential nanocarrier for delivery of morpholinopyrrolizine derivative.

Nose to brain delivery of donepezil through surface modified NLCs: Formulation development, optimization, and brain targeting study

The research was aimed to formulate the Donepezil (DPZ)-loaded nanostructured lipid carriers (NLCs) and coated with chitosan (CH) for brain targeting through the intranasal route. NLCs were prepared by homogenization & sonication technique and optimized by three factors-three levels Box-Behnken design (BBD). The composition of DPZ-loaded CH-NLCs was established by using a mixture of Compritol & Capryol 90 as lipid, poloxamer 188 as a surfactant, and CH as a coating agent. The effect of formulation factors was evaluated on particle size, entrapment efficiency, and polydispersity index (PDI). Finally, ex-vivo permeation, in-situ perfusion as well as in-vivo study was conducted on albino Wistar rats for the detection of pharmacokinetic and neuropharmacokinetic parameters like drug targeting efficiency (% DTE), nose to brain drug transport percentage (DTP), etc of the optimized formulation. Optimized formulation (DPZ-CH-NLCs-OPT2) exhibited an acceptable particle size (192.5 ± 7.3 nm) with 89.85 ± 2.17% entrapment efficiency, 0.298 ± 0.021 PDI, and 38.9 mV zeta potential and particles were spherical shape as shown by TEM. DSC thermogram displayed that the drug existed in amorphous form within the NLCs matrix. Permeability coefficient (Papp) of DPZ-CH-NLCs-OPT2 formulation (10.14 ± 1.73 × 10−3 cm h−1) was two folds than DPZ-Sol (4.55 ± 1.18 × 10−3 cm h−1). The nasal absorption rate constant for DPZ-CH-NLCs-OPT2 (1.4 × 10−3 h−1) was found to be significantly higher than DPZ-Sol (0.5 × 10−3 h−1). The bioavailability of DPZ-CH-NLCs was 2.02 fold than that of DPZ-Sol administered intranasally and 2.41 fold than DPZ-CH-NLCs administered via the intravenous route. Efficient brain targeting and targeting potential was observed as showed by DTE (321.21%) and DTP (74.55%) after intranasal administration of DPZ-CH-NLCs as compared to DPZ-Sol (DTE 158.52% and DTP 36.92%). From the findings, it could be concluded that DPZ-CH-NLCs might be an effective strategy for the brain targeting of DPZ through the intranasal route for the treatment of Alzheimer's disease.

Development and characterization of gastro-floating sustained-release capsule with improved bioavailability of levodopa.

In this study, a new gastro-floating sustained-release capsule (GFC) with levodopa (LD) and benserazide hydrochloride (BH) was successfully developed. GFCs were prepared by filling the LD and BH granules into hard capsules and coated with cellulose acetate (CA) solution as a controlled-release layer. The effects of formulation factors on the release of GFCs were conducted. The AUC0~24 (µgh/mL) of LD were 69.31 ± 3.61 (μgh/mL) and 28.87 ± 2.58 (μgh/mL) and the Cmax were 7.84 ± 0.34 (μg/mL) and 9.21 ± 1.04 (μg/mL) in the GFCs and commercial tablets respectively. The relative bioavailability of LD was 267.55 ± 34.54%. Compared with commercial tablets, the pharmacokinetic study indicated that the developed GFCs provided a better sustained-release effect and higher bioavailability than commercial tablets.

Formulation design, optimization and in vivo evaluation of oral co-encapsulated resveratrol-humic acid colloidal polymeric nanocarriers

The study aims at formulation and optimization of resveratrol and humic acid co-encapsulated colloidal polymeric nanocarriers to improve stability, oral bioavailability, and antiradical activity of water-insoluble, resveratrol. The eudragit E100 polymeric material was used to fabricate resveratrol and humic acid co-encapsulated oral colloidal polymeric nanocarriers (Res-HA-co-CPNs) using emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for oral bioavailability as well as for antiradical potential. Optimized Res-HA-co-CPNs demonstrated spherical and smooth surface including mean particle size, 120.56 ± 18.8 nm; polydispersity index, 0.122; zeta potential, +38.25 mV; and entrapment efficiency, 82.37 ± 1.49%. Solid-state characterization confirmed the amorphous characteristic of optimized Res-HA-co-CPNs. In vitro release profile of Res-HA-co-CPNs showed sustained release behavior up to 48 h and CPNs were found to remain stable at the refrigerated condition for 6 months. In vivo pharmacokinetic studies revealed significant (p < 0.05) improvement of ∼62.76-fold in oral bioavailability. The radical-scavenging activity was found to be increased with time and after 72 h, it was analogous to pure Res. IC50 values were reported to be decreased with time. Henceforth, developed Res-HA-co-CPNs was proven to be a proficient dosage form to increase stability, oral bioavailability, and antiradical activity of resveratrol. Highlights Resveratrol-humic acid co-encapsulated colloidal polymeric nanocarriers (Res-HA-co-CPNs) were fabricated by emulsification-diffusion-evaporation method and optimized by Taguchi orthogonal array design. The Res-HA-co-CPNs revealed favorable mean particle size and percent encapsulation efficiency with a spherical and smooth surface. The Res-HA-co-CPNs showed diffusion-controlled release of Res and were found to be stable at the refrigerated condition for 6 months. The optimized Res-HA-co-CPNs demonstrated significantly (p < 0.05) higher oral bioavailability with respect to pure Res and PM. The optimized Res-HA-co-CPNs demonstrated higher radical-scavenging activity with respect to time.

RESVERATROL-HUMIC ACID LOADED COLLOIDAL POLYMERIC NANOPARTICLES: DESIGN OF EXPERIMENT AND IN VITRO EVALUATION

Objective: The study aims at fabrication and optimization of co-encapsulated resveratrol and humic acid in colloidal polymeric nanocarriers to improves the stability of insoluble antioxidant, resveratrol.&#x0D; Methods: The Eudragit E100 polymeric material was used to fabricate oral co-encapsulation of resveratrol and humic acid in colloidal polymeric nanocarriers, called Res-HA-co-CPNs by an emulsification-diffusion-evaporation method. Taguchi orthogonal array design was employed to check the effect of formulation factors on in vitro physicochemical characteristics. The optimized formulation was further evaluated for stability studies at different conditions.&#x0D; Results: Optimized Res-HA-co-CPNs demonstrated spherical and smooth surface including mean PS 120.56±18.8 nm, PDI 0.122, ZP+38.25mV, and EE 82.37±1.49%. Solid-state characterizations confirmed that optimized Res-HA-co-CPNs showed amorphous characteristics. In vitro release profile of Res-HA-co-CPNs showed an outstanding sustained release behavior up to 48h and remain stable at the refrigerated condition for 6 mo.&#x0D; Conclusion: Res-HA-co-CPNs would be a proficient and promising dosage form for increasing the stability of insoluble antioxidants, resveratrol.

An analysis of the microencapsulation of ceftiofur in chitosan particles using the spray drying technology

Ceftiofur is a third-generation cephalosporin approved to treat numerous infections in production animals. Its commercial formulations are administered daily due to the mean life time, leading to several inconveniences, like operative challenges and non-uniform plasma levels. The objective of this work was to microencapsulate ceftiofur in chitosan particles using spray drying technology to extend the delivery and consequently reduce the dosage frequency. The effect of formulation factors on particle features was studied using a multilevel factorial design. In addition, ceftiofur thermal stability was assayed by differential scanning calorimetry and microbiological assays. Finally, a pharmacokinetic model was developed to predict theoretical plasma concentration in goats. Results showed that ceftiofur thermal stability increased after microencapsulation, indicating a protective effect of chitosan particles. Besides, MIC, IC50 and inhibition halos against E. coli and S. aureus were similar than those of the commercial product. In addition, suitable plasma levels can be theoretically maintained in goats during 48 h with a single injection. These findings suggest that chitosan microparticles could be a good vehicle for ceftiofur administration.

Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed.

The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7–8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.

Continuous twin screw granulation: Impact of the starting material properties and various process parameters

The purpose of this study is to confirm the correlation between the formulation factors and the process parameters using multivariate analysis (MVA) during twin screw granulation. Various grades of lactose and MCC were used as starting materials and the characteristics of final granules were investigated by varying the L/S ratio and feed rate. The size distribution, friability, and various flow properties of granules using powder rheometer were evaluated. When the effect of formulation factors and process parameters were investigated, it was confirmed that the characteristics of granules change largely according to L/S ratio. MVA also showed that the influence of formulation factors on characteristics of granules was significant as L/S ratio. The feed rate had few effects on the characteristics of the granules. MVA is a useful tool to confirm the correlations of various factors. The properties of the starting materials are important in the continuous twin screw granulation process.

Influence of Formulation Factors on the Aerosol Performance and Stability of Lysozyme Powders: a Systematic Approach.

With the growing interest in developing biologics for pulmonary delivery, systematic fast screening methods are needed for rapid development of formulations. Due to the labile nature of macromolecules, the development of stable, biologically active formulations with desired aerosol performance imposes several challenges both from a formulation and processing perspective. In this study, spray-freeze-drying was used to develop respirable protein powders. In order to systematically map the selected design space, lysozyme aqueous pre-formulations were prepared based on a constrained mixture design of experiment. The physicochemical properties of the resulting powders were characterized and the effects of formulation factors on aerosol performance and protein stability were systematically screened using a logic flow chart. Our results elucidated several relevant formulation attributes (density, total solid content, protein:sugars ratio) required to achieve a stable lysozyme powder with desirable characteristics for pulmonary delivery. A similar logical fast screening strategy could be used to delineate the appropriate design space for different types of proteins and guide the development of powders with pre-determined aerodynamic properties.

Improved vaginal retention and enhanced antifungal activity of miconazole microsponges gel: Formulation development and in vivo therapeutic efficacy in rats

Traditional azole antifungal formulations suffer from poor retention in the vaginal cavity, irritation and burning of the vaginal area. In the present work, we aim at the development of a novel miconazole (MCZ) microsponges gel as an attractive dosage form for vaginal candidiasis. The proposed formula has the potential to minimize the local side effects of the drug due to the controlled release characteristic, which increases patient compliance. Moreover, the mucosal retention effect of the microsponges in addition to the bioadhesion property of Carbopol gel prolongs the retention of the dosage form in the vagina and consequently improves the therapeutic efficiency. MCZ microsponges were prepared applying Quasi emulsion method using Eudragit RS100. The effect of formulation factors, namely, drug:polymer ratio (1:1, 2:1 and 4:1), the amount of poly vinyl alcohol (PVA) (25, 50 and 75mg) and the volume of organic solvent (2.5, 5, 10mL) on the characteristics of MCZ microsponges has been investigated. The microsponges were optimized regarding the production yield (68.8±6.4%), particle size (78.2±2.1μm), entrapment efficiency (92.9±1.9%) and release rate (Q150 51.8±2.5%). The selected formula was further evaluated for its, flowability, porosity and surface morphology. MCZ microsponges were incorporated into Carbopol gel, then the viscosity and bioadhesion were examined. The in vitro antifungal activity of MCZ microsponges gel was comparable to the market product. In vivo, MCZ microsponges vaginal gel was more effective than the market product (p<0.05) in eradicating Candida infection in rats, which was supported by the histopathological findings.

Development and optimization of pluronic® F127 and HPMC based thermosensitive gel for the skin delivery of metoprolol succinate

The aim of the present investigation was to prepare and optimize suitable combination of polymers hydroxypropyl methylcellulose (HPMC) and pluronic® F127 (PN F127) for the development of thermosensitive gel of Metoprolol succinate (MS) using central composite design (CCD). The effect of formulation factors (concentration of HPMC and PN F127) on responses such as cumulative percentage release (CPR) of MS, bioadhesive force (BF) and viscosity was measured statistically. Quadratic model was found to be best fit model among different models used in the study. The optimum conditions were found to be 0.92% of HPMC and 15% of PN F127. Under these conditions, the predicted CPR, BF and viscosity were found to be 84.94 μg/cm2, 41.56 gf and 48.94 Pa s, respectively. Ex vivo permeation of MS from optimized thermosensitive gel across abdominal skin of rat demonstrated highest flux (64.35 μg/cm2/h) for the gel formulation containing 1,8-cineole (5% w/w). The hypotensive activity was performed on normotensive rabbits and the results showed that the optimized formulation prolonged the activity up to 12 h. The above findings indicated that thermosensitive gel of MS for skin application exhibited strong potential against hypertension and expected to provide a better alternative to oral MS formulations.

Effect of Formulation Factors on Transcorneal Permeation of Acetazolamide from Aqueous Drops: In vitro andIn vivo Study

Aim: The purpose of this research was to evaluate the effect the formulation factors on in vitro permeation of acetazolamide (ACZ) through freshly isolated goat corneas. Materials and Methods: Different formulation factors were studied. The concentration of drug was raised from 0.025% to 0.1% (w/v) and pH was also varied within the range of 6-8. Several viscosity modifiers and preservatives were also added to study their effect on permeation. Finally, the formulation with the optimized factors was used to study ocular hypotensive activity of the drug in rabbits. Results and Discussion: Raising concentration of the drops from 0.025% to 0.1% (w/v) significantly (P < 0.05), increased drug permeation, but decreased the percent permeation. An increase in the pH of the drops from 6.0 to 8.0 resulted in significant (P < 0.05) change in drug permeation. Eye drops containing benzalkonium chloride (BKC) showed significantly (P < 0.05) higher permeation as compared with control formulation. Compared with control formulation, ACZ 0.1% (w/v) drop containing viscosity modifier produced significant (P < 0.05) decrease in permeation. A formulation having BKC showed increased hypotensive activity as compared to the control formulation. Conclusion: The study reflects that the permeation of ACZ is greatly influenced by formulation factors and permeation was found to be concentration and pH dependent.

Development of sustained release metoprolol succinate matrix tablets using kappa carrageenan as monolithic polymer

The rationale of this research work was to investigate the impending of kappa carrageenans (?C ), for the formulation of sustained-release tablets and to study the factors affecting it. Tablets were compressed on a rotary press and the effect of formulation factors, moisture, and storage on the release of metoprolol succinate was deliberated. The effect of cross-linking salt, potassium chloride, in the tablet formulation and a change in the ionic strength of the dissolution media, was studied on the release of the model drug. The release rate increased both with an increase in tablet diameter. The two lubricants studied had a negligible effect on the rate of drug release at their commonly used concentrations. The moisture content of ?C did not have any significant effect on the release rate. The omission of potassium chloride from the tablets significantly increases the release rate. The change in ionic strength of simulated gastric fluid altered the release rate, highest ionic strength of the dissolution media, showed the least release. ?C tablets were relatively insensitive to small changes in formulation parameters and dissolution conditions.

Liquid–Liquid Phase Separation in a Dual Variable Domain Immunoglobulin Protein Solution: Effect of Formulation Factors and Protein–Protein Interactions

Dual variable domain immunoglobulin proteins (DVD-Ig proteins) are large molecules (MW ∼ 200 kDa) with increased asymmetry because of their extended Y-like shape, which results in increased formulation challenges. Liquid-liquid phase separation (LLPS) of protein solutions into protein-rich and protein-poor phases reduces solution stability at intermediate concentrations and lower temperatures, and is a serious concern in formulation development as therapeutic proteins are generally stored at refrigerated conditions. In the current work, LLPS was studied for a DVD-Ig protein molecule as a function of solution conditions by measuring solution opalescence. LLPS of the protein was confirmed by equilibrium studies and by visually observing under microscope. The protein does not undergo any structural change after phase separation. Protein-protein interactions were measured by light scattering (kD) and Tcloud (temperature that marks the onset of phase separation). There is a good agreement between kD measured in dilute solution with Tcloud measured in the critical concentration range. Results indicate that the increased complexity of the molecule (with respect to size, shape, and charge distribution on the molecule) increases contribution of specific and nonspecific interactions in solution, which are affected by formulation factors, resulting in LLPS for DVD-Ig protein.

Preparation of freeze-dried long-circulation oridonin liposomes and their pharmacokinetics in rats

To prepare freeze-dried long-circulation oridonin liposomes with optimized parameters. Ethanol injection method followed by freeze-drying was used to prepare the liposomes. Sephadex column was used to purify liposomes. Effects of formulation factors on entrapment efficiency of long-circulation oridonin liposomes were studied. The particle size, distribution and in vitro release were determined. Pharmacokinetics of oridonin liposomes in rats was determined by HPLC and the pharmacokinetic parameters calculated by Kinetica(TM) software were compared with conventional oridonin liposomes and solution. The optimized lipid formulation for long-circulation liposomes was composed of soy lecithin, cholesterol and DSPE-PEG 2000 with a ratio of 1:0.5:1.8(w/w). The ratio of drug to lipid was 1:6. Freeze-drying protectant was a mixture of glucose and mannitol (3:1). The entrapment efficiency (EE) of long-circulation oridonin liposomes was about 65%. The particle size of liposomes after hydrolyzation was 164 nm with good DPI. The liposomes showed a sustained drug release in vitro. Intravenous injected oridonin fitted with two-compartment pharmacokinetic model. The MRT of long-circulation liposomes was 2 times and 6 times and AUC was about 2 times and 3 times of conventional liposomes and oridonin solution, respectively. Freeze-dried liposomes with high EE have been obtained by the proposed approach. This long-circulation liposomes extend oridonin half time and significantly increase AUC in rats.

Formulation and biopharmaceutical evaluation of a transdermal patch containing aceclofenac

To reduce the adverse effects of aceclofenac that accompanied with oral administration of this drug, transdermal patches in the form of drug-in-adhesive (DIA) patches, containing aceclofenac, were formulated. The effect of formulation factors on the skin permeation of the drug and physical properties of the patch were evaluated using excised rat skins. The optimized patch contained 12 % aceclofenac and 20 % lauryl alcohol in DT-2852 as a pressure-sensitive adhesive. The pharmacokinetic characteristics of the DIA patch were determined after application of the transdermal patches to human volunteers. The calculated relative bioavailability of the aceclofenac DIA patch was 18.2 % compared to oral administration of the drug. The findings of this study suggest that transdermal application of aceclofenac can substitute for oral administration of the drug.

Effect of formulation factors on in vitro transcorneal permeation of voriconazole from aqueous drops

The purpose of this research was to evaluate the effect the formulation factors on in vitro permeation of voriconazole through freshly isolated goat and sheep corneas. An increase in the pH of the drops from 4.0 to 8.0 resulted in significant (P < 0.05) increase drug permeation. Raising concentration of the drops from 0.05% to 0.2% (w/v) significantly, (P < 0.05) increased drug permeation, but decreased the percent permeation. Corneal transport of voriconazole is both pH and concentration dependent. Eye drops containing disodium edetate (ethylenediaminetetraacetic acid) alone or combination with benzalkonium chloride showed significantly (P < 0.05) higher permeation as compared with control formulation. Addition of beta-cyclodextrin to the formulation enhanced corneal permeation of voriconazole. Compared with control formulation, voriconazole 0.2% (w/v) drop containing viscosity modifier produced significant (P < 0.05) decrease in permeation. Most of the formulations showed higher zone of inhibition against Candida albicans.

Corrosion resistance of lamellar aluminium pigments coated by SiO 2 by sol–gel method

The aluminium pigments were coated with SiO 2 by sol–gel method to improve their stability. The effects of formulation factors, such as medium of reaction, adding sequence of catalyst and number of coating, were investigated. The stability of the coated aluminium pigments in acid was examined by measuring the hydrogen generation amount. It was found that the coating layer formation is due to the condensation of tetraethyl orthosilicate (TEOS) to form a dense 3D cross-linked layer on the surface of aluminium. The optimized sequence of adding catalysts would be hydrochloride first, then ammonia. Stability tests confirmed that the aluminium pigments have better corrosion resistance after coating with SiO 2.

Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium

Levothyroxine is a narrow therapeutic index, and to avoid adverse effect associated with under or excessive dosage, the dose response is carefully titrated. The tablets are marketed with a score providing an option to split. However, there are no systematic studies evaluating the effect of splitting on dose accuracy, and current study was undertaken to evaluate effects of splitting and potential causes for uniformity failures by measuring assay and content uniformity in whole and split tablets. Stability was evaluated by assaying drug for a period of 8 weeks. Effect of formulation factors on splittability was evaluated by a systematic investigation of formulation factors by preparing levothyroxine tablets in house by varying the type of excipients (binder, diluent, disintegrant, glidant) or by varying the processing factors (granulating liquid, mixing type, compression pressure). The tablets were analyzed using novel analytical tool such as near infrared chemical imaging to visualize the distribution of levothyroxine. Assay was not significantly different for whole versus split tablets irrespective of method of splitting (hand or splitter), and splitting also had no measurable impact on the stability. Split tablets either by hand or splitter showed higher rate of content uniformity failures as compared to whole tablets. Tablet splitter produced more fragmentation and, hence, more content uniformity and friability failures. Chemical imaging data revealed that the distribution of levothyroxine was heterogeneous and was dependent on type of binder and the process used in the manufacture of tablets. Splitting such tablets could prove detrimental if sub- or super-potency becomes an issue.