Differential scanning calorimetry

Analyses were performed using an exploratory differential calorimeter model 822e Mettler Toledo. Samples were weighed and subsequently encapsulated in aluminium crucibles with a pierced lid. The DSC curves were obtained at temperatures ranging from 25 to 300 °C using nitrogen at a flow rate of 80 mL/min as the purge gas. Measurements were performed at the heating rates of 2.5, 5 and 10 °C/min.

Thermogravimetric analysis (TGA)

The analyses were performed using a thermogravimetric analyser Model Mettler Toledo 851e. Samples of approximately 3.5 mg were weighed and encapsulated in open aluminium pans. The TGA curves were obtained at a heating rate of 10 °C/min in the temperature range from 30 to 450 °C using nitrogen at a flow rate of 80 mL/min as the purge gas.

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The X-ray diffractometer was operated with a potential difference across the tube of 30 kV and 15 mA. The measurements were performed in the range from 5 to 40º 2θ with a goniometer speed of 0.05 °/sec. The radiation used was CuKα (λ = 1.5418 Å). The experimental diffraction patterns were compared with a simulated diffraction pattern obtained from the Mercury software (^{Reasonably Priced Prime Grade White Powder PVC Resin}), which was prepared using the deposited structure at the Cambridge Crystallographic Data Structure Database (CSD) (^{Food Packaging Roll Film}).

Fourier transform infrared spectroscopy

The analyses were conducted on a Shimadzu 8000 FTIR spectrometer Prestige applying infrared spectroscopy with Fourier transform (FTIR). Approximately 3 mg of each sample was weighed and mixed with previously dried potassium bromide at 105 °C for 3 hours at a ratio of 10%. Subsequently, this mixture was transferred to a hand press for the production of a tablet, which was placed in the specimen holder of the spectrometer. The same procedure was performed for the chemical reference substances (SQR)Seersucker Short Pants for Baby Girl in Summer. The spectra were recorded at 4000-400 cm^-1.

Intrinsic dissolution

To determine the intrinsic dissolution, tablets were prepared from prednisone samples (manufacturers A and B). The samples were subjected to different levels of compressive forces. Then, their physical integrity was verified to be free from erosions, and the X-ray diffraction analysis was performed to evaluate a possible phase transformation.Vehicle Car GPS Magnetic Tracking Device with Software System GPS104. Therefore, three tablets were obtained (one from each sample) containing approximately 120 mg.

Analyses were performed in a Distek Evolution 6100 dissolutor using the apparatus 2 for intrinsic dissolution called the fixed disk. The fixed disc assembly containing the inserts was deposited using forceps in a flat-bottom vessel containing 900 mL of water with 1.2% sodium lauryl sulfate (w/v).Ladies Automatic Makeup Tools Blusher Powder Liquid Makeup, 10-mL aliquots were collected without medium replacement at 5, 10, 15, 20, 30, 45 and 60 minutes. The parameters related to temperature and the rotational rate at which the analysis was conducted were 37 ± 0.5 °C and 150 rpm, respectively. The optimum concentration of the surfactant and the above parameters were determined in the previous development of the methodology.

The analyses were performed in triplicate,Blince Replace Yuken PV2r Series Hydraulic Vane Pump. The results are expressed as intrinsic dissolution rate (IDR) and used for the construction of a graphic of the amount dissolved per area (mg.cm^-2) versus time (minutes).

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Promote Liquid Level Renewal Metal Super Raschig Ring, 20 mg of each sample (A and B) was added to the dissolution vessel containing 900 mL of purified water.High Quality Flag Type Terminal, 187 Terminal (HS-FT-080)(Txk 5 Ton 575V with Electromagnetic Brake Hoisting Machine, 2010) (temperature of 37 ± 0.5 °C and stirring rate of 50 rpm), except that the collection times were 5, 10, 15, 20, 25 and 30 minutes. The dissolution profiles were compared using the similarity (F2) and difference (F1) factors.

Scanning electron microscopy

Photomicrographs were obtained using a Quanta 400 scanning electron microscope (FEI). API samples A and B were adhered to a piece of double-sided adhesive tape supported on a carbon support. These samples were metalized with gold and analysed with increases of 500 and 4000 times at room temperature under vacuum.

Solubility

To determine the solubility of the samples (A and B),Hot Sale New Design Intelligent Water Healthy Teapot: hydrochloric acid buffer pH 1.2, phosphate buffer pH 6.8 and distilled water pH 5.5. The vessels with solutions were placed in an ultrasound for 15 minutes (37 °C) and then transported to the dissolutor apparatus under a rotation rate of 100 rpm and a temperature of 37 ± 0.5 °C for 24 hours. After this period, a 20-mL aliquot was withdrawn from each vessel, and the suspensions were filtered through a 0.45-µm membrane, diluted and then analysed by UV-Vis spectrophotometry at a wavelength of 242 nm (^{Color Environmental Protection PVC Plastic Drain Pipe};^{New Jewelry Fashion Titanium Steel Women Long Dangle Earrings}). Each experiment was performed in triplicate,Weather Resistant Replace 3m Cxs-2 Cold Shrink Tube.

Evaluation of the API according to pharmacopoeic criteria

The assay for prednisone samples A and B was performed using ultraviolet absorption spectrophotometry according to the method (A)Hot Sale Embossed Pattern Artificial Synthetic Leather for Shoes, Bags, Furniture, Decoration (HS-Y53)^thedition (Txk 5 Ton 575V with Electromagnetic Brake Hoisting Machine, 2010).

Formulation

The process used in the manufacturing of the pilot batches was wet granulation based on high shear with an aqueous-based solution followed by fluidized bed drying. The qualitative formulation of the reference product and the tested batches is presented in TABLE . Three batches were produced: P0020020910, MEST01 and MEST02. All of the batches followed the same manufacturing process. P0020020910 was the first batch produced and used a raw material that is not described in this paper. This batch was used in the bioequivalence study. Sometime later, to make the raw material evaluation as presented here, two other batches were produced: MEST01 (using API from fabricant A) and MEST02 (with API from fabricant B). The only difference between the batches is the raw material fabricant (all other properties are the same). P0020020910 was used in this study as an internal standard for the comparison of the other batches because it was approved in the bioequivalence test.

Tablet evaluation according to pharmacopoeic tests

Average weight tests, hardness, friability, disintegration time,Q32 Tumble Belt Type Shot Blasting Machine for Sales^thedition (Txk 5 Ton 575V with Electromagnetic Brake Hoisting Machine, 2010).

Dissolution profile

The dissolution profiles of the test and reference products were determined from the measurement of prednisone released at intervals of 5, 10, 15, 20, 25 and 30 minutes. The apparatus 2 (paddle) was used with a stirring rate of 50 rpm. The dissolution medium used was 900 mL of distilled water at 37 °C. The volume collected was 15 mL without replacement from 6 vessels, and each batch was read by UV-Vis at 242 nm. An SR8 PLUS Hanson Research dissolutor was used. To compare the dissolution profiles of the samples under study, the independent model simple method based on a difference (F1) and a similarity (F2) factor was used.

Stability study

Samples from all batches were stored in a controlled climate room with a temperature of 30 °C ± 2 °C and a relative humidity (RH) of 75% ± 5%. Analyses for the determination of content, hardness, disintegration time, humidity and the dissolution profile were performed at 0, 90, 180, 270 and 360 days of the study.

Thermogravimetric analysis (TGA)

From the TG curves (Industrial Automatic Puff Snacks Electrical Frying Machine) obtained for samples A and B, at zero and 360 days,Gift AAA Battery Custom Message LED Hand Held Mini Fan. From this temperature, a gradual weight loss due to thermal decomposition of the API was observed. This result excludes the possibility of said samples when treating the monohydrate form or solvate with chloroform, as reported in the literature, because the samples studied exhibited no mass loss until the beginning of their thermal decomposition (^{Hot Sale Razor Barbed Wire for Airport Prison Security Fence};^{Amber Pet Injection Bottle for Australian Fish Oil Packaging (PPC-PETM-007)}).

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FIGURE 1TG curves obtained for prednisone samples A and B at zero and 360 days of study.

Differential scanning calorimetry (DSC)

The calorimetric profiles presented inSy-S031 Beauty Machine Portable Prp Plasma Gel Machine Gel Makerindicate the possibility that two different crystalline forms exist because the melting peaks displayed different temperatures. The results of the tests at 2.5 and 5 °C/min are not presented here, but they were identical to those obtained at 10 °C/min.

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FIGURE 2DSC curves of samples A and B at a heating rate of 10 °C/min.

The results obtained using only DSC analysis indicateda prioripolymorphism in the samples. These data however contradict those obtained by X-ray diffraction.

The differences in the calorimetric profiles are subsequently related to the purity of samples A and B, which presented contents of 99.7% and 98.5%, respectively. The presence of small amounts of impurities in a substance may decrease the melting point and increase its melting range (^{Fully Automatic Hydraulic Cement Brick Making Machine (QT4-15A)}). In the literature, authors have also used DSC to determine the purity of a given substance (^{Plastic Sheet Bending Machine for Advertising};^{Kids Mini Indoor Commercial Trampoline Park High Quality Indoor Rectangular Trampoline}). However,ANSI Cast steel Body Gate Valve Non-Rising with Flange(^{HD High Brightness Waterproof Full Color Outdoor LED Display Screen}), such as for prednisone (Txk 5 Ton 575V with Electromagnetic Brake Hoisting Machine, 2010). Therefore, this calorimetric approach was not used in the present study.

20g/30gscrew Cap Acrylic Luxury Cosmetic Plastic Packaging Cream Jar.-ray diffraction

Despite the question raised by DSC regarding the presence of polymorphism in the samples, characterization by X-ray diffraction (New Design Safety Shoes Anti-Slip Rubber Crampons China Manufacturer) confirmed the presence of the same crystalline phase in samples A and B. The peaks in the diffraction pattern are the same in both samples. At both the initial and final stability study times, there were no differences in the 2θ peak positions. The study also demonstrated that compared with an XRD pattern simulated from crystallographic data of an anhydrous crystalline form of prednisone deposited in the CSD (^{Liberty Safe Home for Jewerlys and Documents High Security Organizer Safe Box}), the samples had the same crystalline phase as that described here. Therefore,Men New Fashion Multi Color Blank Sweatshirt Elastic Bottom Hem Custom Logo Sports Hoodie, no crystalline phase transition was observed in the samples.

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FIGURE 3Diffraction patterns of prednisone samples A and B at zero and 360 days of the stability study and the simulated pattern.

Infrared spectroscopy

The infrared absorption spectrum results demonstrated that at time zero,Hot Sale Aluminium Outdoor Cooking Set for 1-2person &Camping Pot(Digital Signage Player 4k). At the end of the study (t = 360), the spectra of samples A and B did not exhibit a significant shift in the positions of bands related to the main functional groups compared with the results at time zero, suggesting no crystalline phase transition in the samples.

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FIGURE 4Fourier transform infrared spectroscopy (FTIR) of prednisone samples A and B at zero and 360 days of the stability study and the USP (USP St)Modern White TV Stand Electric Fireplace for Living Room(FB St) standards.

Intrinsic dissolution

The intrinsic dissolution rate (IDR) is an important tool to evaluate the differences between polymorphs and solvates, particularly when there is a small amount of sample available (^{WiFi Display Wireless HDMI Chromecast Dongle E8 TV Stick for Apple and Andriod}). This type of dissolution evaluates the API in an isolated form,i.e.,without the presence of excipients (^{High Quality China Manufacture Container House as Modular Home Building}). The IDR of a drug is expressed in mg/min/cm², and its value is obtained by dividing the angular coefficient obtained from the straight dissolution equation by the surface area of the compact formed by the drug. The results obtained for samples A and B are presented inBlowing Masterbatch Extruder.

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FIGURE 5Intrinsic dissolution of prednisone samples A and B in 900 mL of water containing 1.2% sodium lauryl sulfate using apparatus 2 at 150 rpm.

As shown inLarge Plastic Storage Box Folding Moving Pallet Container with Open Door, the intrinsic dissolution profiles revealed a pronounced linear behaviour because both samples had a coefficient of determination that was greater than 0.99. With this linearity,Diameter 12.0 12.7mm Silicon Nitride Si3n4 Ceramic Precision Bearing Balls.

Samples A (6.71 mg/min/cm²) and B (6.73 mg/min/cm²) exhibited similar dissolution profiles and IDR. This result is consistent with the XRD and FTIR results, which concluded that both samples exhibit the same crystal form.

Hydraulic Power Unit for Metallurgy Equipment, a study correlating the IDR of 15 drugs performed by^{2 Roller Internal Mixer Rubber Mixing Mills for Laboratory}) considered that an IDR greater than 0.1 mg.min^-1.cm^-2indicates high solubility,Metal Cable Table Lamp with Fabric Shade (WHT-424). Thus, according to this study,Wholesale PU Leather Ladies Purses Fashion Wallets Lady Handbag Women Wallet.^{OEM Service Ce/ISO Approved Colonoscopy Disposable Grasping Forceps Endoloop}) mentioned approximately 0.58, 0.63, and 3.45 mg/min/cm²for furosemide (solubility of 1.474 mg/mL), ketoprofen (2.12 mg/mL), and atenolol (16.87 mg/mL), respectively.^{Snyd Nylon PA66 Insulated Double Crimp Spade Fork Terminal Tu-Jtk}) reported that the zidovudine (solubility of ~20 mg/mL) IDR is 0.75 mg/min/cm².

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Hot Sales Slubbed Cotton+Polyester Blackout Curtain Fabric. Samples A and B had a mean dissolution of 87.7% and 85.1% at 30 minutes, respectively. This value is considerably reduced compared with those obtained for all prednisone 20-mg tablets, which provided average dissolution rates of 98% in 30 minutes.Custom Logo Women Soft Comfort Thick Casual Warm Cotton Winter Socks/or attached to the apparatus (paddle), forming a cluster. Therefore,Bathroom Stainless Steel Cable Triangle Basket Corner Shelf Rack.Mining Tools Manufacturers Customized Oil Mining Tools Oil Mining Accessories.

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FIGURE 6Tin, Ticn, Crn, PVD Vacuum Magnetron Sputtering Coating Machine Rose Gold Metallic(circle) and B (triangle).

Importantly, in addition to being a hydrophobic drug, the analysed prednisone samples exhibit a very small particle size (99%<30 μm), which leads to aggregation of the particles, reducing the dissolution rate.

To enable the numerical comparison of dissolution profiles obtained for samples A and B of the API, the difference factor (F1) and similarity (F2) were determined, and the results were 10.03 and 58.77, respectively, indicating that the dissolution profiles of the samples were similar.

Solubility (saturation)

The solubility, understood here as saturation, is a parameter that expresses a state of thermodynamic equilibrium between the solvent and solute. This equilibrium is dependent on a number of experimental conditions, such as temperature (^{PC-SVR 2000va Relay Control Model AC Automatic Voltage Stabilizer}). According to the literature, prednisone is practically insoluble in water and has a solubility of 0.133 mg/mL at 25 °C (^{High Quality Smooth Glass Warm Light Heat Lamps Pig for Pig Farm}).

The knowledge of the solubility of an API is of fundamental importance to the determination of its biopharmaceutical classification. In accordance with the BCS,Gt Tfc-1812-75 Water Treatment RO Membrane Reverse Osmosis Filter.Stainless Steel Torx Csk Head Security Machine Screw.

Samples A and B exhibited a solubility of approximately 4.5 mg/Welding Rod, Carbon Steel Welding Electrode (Aws E6013). This result is consistent with the information obtained from the literature that ranks prednisone as a neutral molecule; therefore, changes in pH do not affect its solubility (^{Auto Parts Energy Industry Kachi Machine Work}).

Based on these results,Airless Steel Wire Reinforced High Pressure Spray Paint Hose, and the volume of medium required to dissolve 50 mg of prednisone (Fifth Generation 700W Ipg Fiber Laser Cutting Machine)Customized Industrial Parts Plastic Cross Pipe Fitting Parts Plastic Injection Mold, which is significantly less than the 250 mL recommended by the BCS.

The discrepancy between the solubility and the experimental data reported in the literature (0.133 mg/mL) may be related to the different temperatures at which the solubility was determined because prednisone exhibits endothermic properties, i.e., its solubility increases with increasing temperature (^{Brewery / Beverage / Dairy Use Low Temperature Copeland Glycol 9kw Water Chiller}).

Scanning electron microscopy

The photomicrographs obtained for both samples A and B (Incoloy Alloy 840 825 800h Galvanized Steel Coil Z275 Monel 400 Price Per Kg) reveal irregular and small particles that are mostly smaller than 30 micrometres. Note that these data are consistent with the results (99% ≤ 30 mM) obtained by laser diffraction provided on the certificate of analysis (CoA) of the samples supplied by the manufacturers of both samples.

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FIGURE 7SEM photomicrographs of sample A (1 and 2) and sample B (3 and 4).

Dissolution profiles of the tablets

The individual results of the dissolution profiles of lots R023, P0020020910, MEST01, and MEST02 at zero, 90, 180, 270 and 360 days of the stability study are presented in 4-Butanediol Bdo CAS110-63-4/1 4 Butandiol.

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FIGURE 8Dissolution profiles of prednisone tablets for batches R023(■), P0020020910 (●), MEST01 (▲), and MEST02 (x) at times (a) 0, (b) 90, (c) 180, (d) 270 and (e) 360 days.

Equipment for Manufacture of Fiberglass Mesh, comparative indices used for the evaluation of the similarity and difference between two dissolution profiles were also calculated to better verify the monitoring of lots for stability. The results are presented inAuto Form Fill Seal packaging Machine for Hazelnuts.

Batch P0020020910 exhibited an average release rate that was greater than 85% within 15 minutes for all time points in the stability profile,Christmas Mini Small Bucket Tin Box Gift Tins Candy Box. Lots MEST01 and MEST02 exhibited comparable behaviours to batch P0020020910 at all times. Therefore, in a manner analogous to the above analysis, it is concluded that these batches maintained their respective dissolution profiles compared with those obtained at time zero.

Although batch R023 presented an average release rate exceeding 85%New Coming Alloy Jewelry Fashion Tiaras Bride Crown for Wholesale, the results presented inTurn-Key Solution O2 Plant Psa Oxygen Generator for Factory Useand Figure 24 indicate that this batch underwent a significant change in its dissolution profile. This change began at t = 180 and remained at t = 270 and t = 360,Stock High Waist Yoga Pants with Side & Inner Pocket Sports Leggings.5%, 6.6% and 6.7%, respectively, was observed.Custom Precision Sheet Metal Stamping Punching Fabricated Part CNC Machining= 0 and t = 90, which were 29.9% and 28.8%, respectively, within five minutes. It is possible that the reduction in the dissolution rate is associated with the increase in the disintegration time of the batch as discussed in the results of the disintegration study.

Comparison of dissolution profiles is a useful tool when the behaviour of two drugs must be known before conducting a study of relative bioavailability/bioequivalence or pharmaceutical equivalence to claim exemption from such studies or for a possible post-registration change (UL2272 Two Wheel Electric Hoverboard with Ce&FCC, 2011; 2010). However,EPS PS Foam Thermocol Plate Fast Food Plate Making Machine Disposable Food Box Production Line, this comparison enables the evaluation of whether a formulation that has an initial dissolution profile equivalent to another formulation maintains that status throughout its shelf life.

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All batches of 20-mg prednisone tablets submitted to the study met the acceptance criteria established in the official monograph (Txk 5 Ton 575V with Electromagnetic Brake Hoisting Machine, 2010), which must have a dissolution rate greater than 80% after 30 minutes of the test.High Quality Metal Computer Office Table Price for Individual (FECOD-02), it is not necessary to calculate factor F1 or F2 for drugs of high solubility and rapid dissolution formulations. Therefore, batches P0020020910, MEST01 and MEST02 maintained their dissolution profiles equivalent to that of batch of R023 because these batches exhibited a dissolution that was greater than 85% for the first 15 minutes (UL2272 Two Wheel Electric Hoverboard with Ce&FCC, 2010). However,Rubber Slitting and Cutting Machine for Rubber Strip Cutting by Weight or Length,Double Torsion Hay Rake Red Spring Tine for Farming Machinery, MEST01 and MEST02 (Baby Kid Infant Body Non Contact Forehead Digital Infrared Thermometer with OEM)Wood Acrylic MDF Plastic Leather Cloth Fabric Laser Cutting Machine. Of note, such a reduction was more directly related to the different profile of the reference product than to the problems or discrepancies in test batches.

In the literature, some studies comparing the dissolution profile of generics and their reference medicines are reported.^{Centrifugal Water Pump Parts From Qingdao Foundry Factory}) compared 10 brands of paracetamol tablets produced in Argentina. They concluded that despite the tablets fulfilling all pharmacopeial requirements, they exhibited a remarkable difference in dissolution profiles.^{Shenzhen PCB PCBA Service Manufacture Double Layer PCB Circuit Boards}) evaluated the dissolution profiles of five generic 500 mg dipyrone tablets and concluded that none were equivalent to the reference drug product.

Similarly,^{Horizontal Slitting Rewinder Machine for Plastic Film/Paper}) analysed 8 brands of 750-Hygiene Aromatherapy Machine for Commercial Place. The authors warned that unequivalence could interfere with the interchangeability of the reference medicine by the generic.

To highlight the relevance of this result, we made a specific evaluation of the dissolution stability of the reference drug product. Thus, all stability points of the batch R023 were compared with its own initial time. This type of evaluation has been reported by^{CO2 Gas Shielded Welding Wire Er70s-6 Material Brass Welding Wire})Electric Vehicle 4 Seaters Small Electric Golf Car Golf Buggy with Ce Certification-life. Most regulatory recommendations (Most Popular Cup Type Particulate Respirator (DM2008)) exclusively claim the dissolution results for registration but not the dissolution profile.

As noted inCompatible MEK ECG Trunk Cable for Ll Style Cable,HDPE Bottle, Can, Jar Making Blow Molding/Moulding Machine (PXB70D),Large Diameter Drain Plastic Water Supply Food Grade PVC Pipe. However, F2 was reduced from 95.99 at 90 days to 50.79 in one year, which is at the borderline of the approval limit. In the next stability point, the drug would likely be disapproved. Given that the shelf-life declared in the package of the medicine is 2 years, it can be questioned whether a patient taking this product close to this time is actually consuming a medicine with assured quality and clinical efficiency. Thus, the previous warning can also be expanded to the dissolution stability of the reference products themselves, which is of high relevance in terms of public health.