Numerical study of drop dynamics for inkjet based 3D printing of pharmaceutical tablets.

Interest in 3D printing has been growing rapidly especially in pharmaceutical industry due to its multiple advantages such as manufacturing versatility, personalization of medicine, scalability, and cost effectiveness. Inkjet based 3D printing gained special attention after FDA's approval of Spritam® manufactured by Aprecia pharmaceuticals in 2015. The precision and printing efficiency of 3D printing is strongly influenced by the dynamics of ink/binder jetting, which further depends on the ink's fluid properties. In this study, Computational Fluid Dynamics (CFD) has been utilized to study the drop formation process during inkjet-based 3D printing for piezoelectric and thermal printhead geometries using Volume of Fluid (VOF) method. To develop the CFD model commercial software ANSYS-Fluent was used. The developed CFD model was experimentally validated using drop watcher setup to record drop progression and drop velocity. During the study, water, Fujifilm model fluid, and Amitriptyline drug solutions were evaluated as the ink solutions. The drop properties such as drop volume, drop diameter, and drop velocity were examined in detail in response to change ink solution properties such as surface tension, viscosity, and density. A good agreement was observed between the experimental and simulation data for drop properties such as drop volume and drop velocity.

Mitigation of Tribocharging in Pharmaceutical Powders using Surface Modified V-Blenders.

INTRODUCTION: The pharmaceutical industry involves handling of powders on a large scale for manufacturing of solid dosage forms such as tablets and capsules constituting about 85% of the dosage forms. During this manufacturing process, powders get electrostatically charged due to numerous particle-particle and particle-equipment wall collisions. Most of the pharmaceutical powders are insulators in nature and they accumulate charge for longer durations making it difficult to dissipate the generated charge. In this study, a surface modified blender has been used to analyze tribocharging in pharmaceutical powders. METHODS: The surface modified blender has been fabricated using two types of materials, an insulator, and a conductor. The conductor or the metal arm induces charge of opposite polarity to that of the charge induced by the insulator arm and the overall charge on the powder decreases during the tumbling motion of the blender. Ibuprofen was used as the model drug and processed in aluminum, polyvinyl chloride (PVC), stainless steel, surface modified aluminum-PVC (Al-PVC) and surface modified stainless steel- PVC (SS-PVC) blender at 20% RH for different blending times such as 2, 10, 20, 30 and 40 min. To better understand the tribocharging phenomenon in surface modified V blenders, an experimentally validated computational model was developed using Discrete Element Method (DEM) modeling. RESULTS: Significant reduction (> 50%) in electrostatic charge was observed for Ibuprofen using surface modified blenders in comparison to metal only and insulator only V blenders. Additionally, an identical charging trend was observed between the simulation and experimental data.  CONCLUSION: It was established that careful selection of equipment materials could significantly reduce the electrostatic charging of pharmaceutical powders and DEM model could be a really useful tool in assessing the applicability of the modified V blenders.

Large-Scale Freeze-Thaw of Protein Solutions: Study of the Relative Contributions of Freeze-Concentration and Ice Surface Area on Stability of Lactate Dehydrogenase.

Although bulk biotherapeutics are often frozen during fill finish and shipping to improve their stability, they can undergo degradation leading to losses in biological activity during sub-optimal freeze-thaw (F/T) process. Except for a few small-scale studies, the relative contribution of various F/T stresses to the instability of proteins has not been addressed. Thus, the objective of this study was to determine the individual contributions of freeze-concentration, ice surface area, and processing time to protein destabilization at a practical manufacturing-scale. Lactate dehydrogenase (LDH) in histidine buffer solutions were frozen in 1L containers. The frozen solutions were sliced into representative samples and assessed for the ice specific surface area (SSA) and extent of solutes freeze-concentration. For the first time to our knowledge, ice SSA was measured in dried samples from large-volume protein solutions using volumetric nitrogen adsorption isotherms. SSA measurements of the freeze-dried cakes showed that the ice surface area increased with an increase in the freezing rate. The ice SSA was also impacted by the position of the sample within the container: samples closer to the active cooled surface of the container exhibited smaller ice surface area compared to ice-cored samples from the center of the bottle. The freeze-concentrate composition was determined by measuring LDH concentration in the ice-cored samples. The protein distributed more evenly throughout the frozen solution after fast freezing which also correlated with enhanced protein stability compared to slow freezing conditions. Overall, better protein stability parameters correlated with higher ice SSA and lower freeze-concentration extent which was achieved at a faster freezing rate. Thus, extended residence time of the protein at the freeze-concentrated microenvironment is the critical destabilizing factor during freezing of LDH in bulk histidine buffer system. This study expands the understanding of the relative contributions of freezing stresses which, coupled with the knowledge of cryoprotection mechanisms, is imperative to the development of optimized processes and formulations aiming stable frozen protein solutions.

Pharmaceutical applications of powder-based binder jet 3D printing process - A review.

Pharmaceutical applications of the 3D printing process have recently matured, followed by the FDA approval of Spritam, the first commercial 3D printed dosage form. Due to being a new technology in the conventional dosage formulation field, there is still a dearth of understanding in the 3D printing process regarding the effect of the raw materials on the printed dosage forms and the plausibility of using this technology in dosage development beyond the conventional ways. In this review, the powder-based binder jet 3D printing (BJ3DP) process and its pharmaceutical applications have been discussed, along with a perspective of the formulation development step. The recent applications of BJ3DP in pharmaceutical dosage development, the advantages, and limitations have further been discussed here. A discussion of the critical formulation parameters that need to be explored for the preformulation study of the solid oral dosage development using the BJ3DP process is also presented.

Formulation design for inkjet-based 3D printed tablets.

The drug loading efficiency was evaluated using a binder-jet 3D printing process by incorporating an active pharmaceutical ingredient (API) in ink, and quantifying the printability property of ink solutions. A dimensionless parameter Ohnesorge was calculated to understand the printability property of the ink solutions. A pre-formulation study was also carried out for the raw materials and printed tablets using thermal analysis and compendial tests. The compendial characterization of the printed tablets was evaluated with respect to weight variation, hardness, disintegration, and size; Amitriptyline Hydrochloride was considered as the model API in this study. Four concentrations of the API ink solutions (5, 10, 20, 40 mg/mL) were used to print four printed tablet batches using the same tablet design file. The excipient mixture used in the study was kept the same and consists of Lactose monohydrate, Polyvinyl pyrrolidone K30, and Di-Calcium phosphate Anhydrate. The minimum drug loading achieved was 30 µg with a minimal variation (RSD) of <0.26%. The distribution of the API on the tablet surface and throughout the printed tablets were observed using SEM-EDS. In contrast, the micro-CT images of the printed tablets indicated the porous surface structure of the tablets. The immediate release properties of the printed tablets were determined using a dissolution study in a modified USP apparatus II.

Triad of Idiopathic Thrombocytopenic Purpura, Preeclampsia, and HELLP Syndrome in a Parturient: A Rare Confrontation to the Anesthetist.

Idiopathic thrombocytopenic purpura (ITP) with HELLP represents a rare complication that requires combined care of obstetrician, anesthesiologist, hematologist, and neonatologist. At 37-week gestation a 35-year-old parturient (G2A1P0) a known case of chronic ITP presented with severe pregnancy induced hypertension (PIH), thrombocytopenia, and elevated liver enzymes. We describe successful anesthetic management of this patient who was taken for emergency caesarean section.

A comparison of conventional endotracheal tube with silicone wire-reinforced tracheal tube for intubation through intubating laryngeal mask airway.

BACKGROUND: A specially designed wire-reinforced endotracheal tube - the Fastrach silicone tube (FTST) designed to facilitate endotracheal intubation through intubating laryngeal mask airway (ILMA) are expensive and not readily available. Hence, it is worth considering alternative such as polyvinyl chloride tracheal tube (PVCT), which is disposable, cheap and easily available. The aim of the present study was to compare the clinical performance of FTST with conventional PVCT for tracheal intubation through ILMA. METHODS: After informed consent, 60 ASA I-II adults with normal airway undergoing elective surgery were randomly allocated to undergo blind tracheal intubation through ILMA with a FTST or conventional PVCT. Overall success rate, ease of insertion, number of attempts for successful intubation, critical incidence during intubation and post-operative sore throat were compared. RESULTS: The overall success rate with FTST was 96.63% and 93.33% with PVCT; in addition, the first-attempt success rate was 86.25% with FTST compared to 82.14% with PVCT. The time taken for intubation was 18.6 ± 6.8 s. in FTST group and 22.42 ± 8.5 s. in PVCT group. Incidence of sore throat was 21.42% in PVCT group compared with 6.89% in FTST group. CONCLUSION: Blind tracheal intubation through an ILMA with the conventional PVCT instead of FTST is a feasible alternative in patients with normal airways.

Analgesic efficacy of peritubal infiltration of ropivacaine versus ropivacaine and morphine in percutaneous nephrolithotomy under ultrasonic guidance.

BACKGROUND AND PURPOSE: Percutaneous nephrolithotomy is a safe and effective endourologic procedure which is less morbid than open surgery. However, pain around a nephrostomy tube requires good post-operative analgesia. We hypothesize that infiltration of local anesthetic with opioid from the renal capsule to the skin around the nephrostomy tract under ultrasonic guidance would alleviate the postoperative pain for a long period. METHODS: A total of 60 ASA physical status I to II patients were selected for a prospective randomized double-blind controlled study in percutaneous nephrolithotomy surgeries. Patients were divided into group R (n=30) and group RM (n=30). Balanced general anesthesia was given. After completion of the surgical procedure, a 23-gauze spinal needle was inserted at 6 and 12 O'clock position under ultrasonic guidance up to renal capsule along the nephrostomy tube. A 10 ml drug solution was infiltrated in each tract while withdrawing from renal capsule to the skin. After extubation, the patient was shifted to the post-anesthesia care unit for 24 hours. Post-operative pain was assessed using the visual analog scale (VAS) and dynamic visual analog scale (DVAS) (during deep breathing and coughing) rating 0-10 for initial 24 hours. Rescue analgesia was given in the form of injection tramadol 1.0 mg/kg intravenously when VAS ≥4 and maximum up to 400 mg in 24 hours. Time to 1(st) rescue analgesic, number of doses of tramadol and total consumption of tramadol required in initial 24 hours were noted. Patients were observed for any side effect and treated accordingly. RESULTS: Time to 1(st) rescue analgesic, i.e., duration of analgesia in group RM is more prolonged than group R (P=0.0004). The number of doses of tramadol in 24 hours in group R were higher as compared to group RM (P=0.0003). The total amount of tramadol in 24 hours in group R was more than in group RM (P=0.0013). Side effects like nausea and vomiting and sedation were comparable in both the groups. CONCLUSION: Addition of morphine to ropivacaine for nephrostomy tract infiltration significantly prolonged the duration of post-operative analgesia and reduced the number of doses and total consumption of rescue analgesic in initial 24 hours in percutaneous nephrolithotomy surgery.

The analgesic efficacy of ultrasound-guided transversus abdominis plane block for retroperitoneoscopic donor nephrectomy: A randomized controlled study.

BACKGROUND: Transversus abdominis plane (TAP) block is suitable for lower abdominal surgeries. Blind TAP block has many complications and uncertainty of its effects. Use of ultrasonography increases the safety and efficacy. This study was conducted to evaluate the analgesic efficacy of ultrasound (USG)-guided TAP block for retroperitoneoscopic donor nephrectomy (RDN). METHODS: In a prospective randomized double-blind study, 60 patients undergoing laparoscopic donor nephrectomy were randomly divided into two groups by closed envelope method. At the end of surgery, USG-guided TAP block was given to the patients of both the groups. Study group (group S) received inj. Bupivacaine (0.375%), whereas control group (group C) received normal saline. Inj. Tramadol (1 mg/kg) was given as rescue analgesic at visual analog scale (VAS) more than 3 in any group at rest or on movement. The analgesic efficacy was judged by VAS both at rest and on movement, time tofirst dose of rescue analgesic, cumulative dose of tramadol, sedation score, and nausea score, which were also noted at 30 min, 2, 4, 6, 12, 18, and 24 h postoperatively. Total tramadol consumption at 24 h was also assessed. RESULTS: Patients in group S had significantly lower VAS score, longer time tofirst dose of rescue analgesic (547.13±266.96 min vs. 49.17±24.95 min) and lower tramadol consumption (103.8±32.18 mg vs. 235.8±47.5 mg) in 24 h. CONCLUSION: The USG-guided TAP block is easy to perform and effective as a postoperative analgesic regimen in RDN, with opioids-sparing effect and without any complications.

Post operative analgesia after incisional infiltration of bupivacaine v/s bupivacaine with buprenorphine.

INTRODUCTION: Opioid receptors have been demonstrated in the peripheral nerve endings of afferent neurons. Blockade of these receptors with peripherally administered opioid is believed to result in analgesia. AIM: To evaluate whether buprenorphine added to bupivacaine for wound infiltration can enhance post-operative analgesia via peripheral mechanisms. MATERIALS AND METHODS: Forty ASA I and II adult patients scheduled for open donor nephrectomy were enrolled in this randomized double blind prospective study. In group A (n = 20) patients, the wound was infiltrated with bupivacaine 0.5% (2 mg/kg) and in group B (n = 20) with bupivacaine 0.5% (2 mg/kg) and buprenorphine (2 µg/kg). All patients were given diclofenac 75 mg IM at 8 h interval. Post-operative quality of analgesia was assessed by VAS (0-10) for 24 h and when VAS > 4 rescue analgesic was administered. Total dose of rescue analgesic and side effects were noted. RESULTS: The time of administration of first rescue analgesic was significantly higher in group B (10.52±5.54 h) as compared to group A (3.275±1.8 h). Mean VAS was significantly lower in group B as compared to group A. The total dosage of rescue analgesic was more in group A as compared to group B patients. CONCLUSION: Addition of buprenorphine to the local anesthetic significantly prolonged the time to first rescue analgesic requirement and the total consumption of rescue analgesic in 24 h, thus providing evidence in support of the existence of peripheral opioid receptors.