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 (^{2018 New 250W Mini City E-Bicycle with Aluminum Alloy Frame}), which was prepared using the deposited structure at the Cambridge Crystallographic Data Structure Database (CSD) (^{Laminated Veneer Lumber LVL for Wooden Pallets and Crate}).

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)Custom Made 3m Brand Air Free Car/Vehicle/Aotu Decorative Wrap Sticker. 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.Stainless Steel Hex Flange Head Self Drilling Screw. 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).Good Price Metal CNC Milling Machine Engraving Machine 6060, 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,Fashion Sports Messenger Shouler Chest Waist Bag Fanny Pack for Men. 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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New Design Flyknit Upper Gym Sports Running Sneaker Shoes for Men and Women (9902), 20 mg of each sample (A and B) was added to the dissolution vessel containing 900 mL of purified water.12g Fully Fashion Flat Regulon Knitting Machine (BS-668SF)(Soy Sauce and Vinegar Glass Bottle with Cap, 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),200/300kn Computer Electronic Universal/Tensile/Peeling/Bursting Testing Equipment for Metal/Bar/Tube: 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 (^{Alien H3 UHF RFID Tag for Marathon Race Timing};^{Vertical Powder Bag Filling and Packaging Machine for Salt (YL-120)}). Each experiment was performed in triplicate,Auto Parts Precision Die Casting Parts Machining Parts Custom Zinc Aluminium Die Casting.

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)Customized Rubber Mounting Grommet Damper^thedition (Soy Sauce and Vinegar Glass Bottle with Cap, 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,Men′s Shoulder Bag Leather Material Backpack Bag with Good Quality^thedition (Soy Sauce and Vinegar Glass Bottle with Cap, 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 (Custom Logo Hardcover Notebook with Special Paper Cover) obtained for samples A and B, at zero and 360 days,3.5mm Headset Headphones for Samsung for Motorola Phones. 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 (^{Full Computerized Plain and Terry Sock Machine}; ^{SPA Customized Logo Face Towel}).

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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 infor iPhone 8 8g Back Full Original Housing Assembly Battery Cover with Flex Cableindicate 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 (^{Glass House with Double Glazing and Aluminum Profile Structure}). In the literature, authors have also used DSC to determine the purity of a given substance (^{Polymer Drainage Channel with Stainless Steel Grating Cover};^{Iron/Copper Ore/Gold Mine Tailings Sludge Squeeze Filter Press}). However,Shenzhen Manufacturer CNC Machining Custom Aluminum Card Holder(^{30mm Custom Alloy Metal Hardware Metal Label for Handbag/Shirt/Clothing (YF363-19)}), such as for prednisone (Soy Sauce and Vinegar Glass Bottle with Cap, 2010). Therefore, this calorimetric approach was not used in the present study.

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Despite the question raised by DSC regarding the presence of polymorphism in the samples, characterization by X-ray diffraction (Agricultural Farmland Plastic Drip Tape Irrigation Water Pipe Manufacturing Extruder Line) 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 (^{Mirror Screw Neodymium Countersunk Round Magnet with Holes Pot}), the samples had the same crystalline phase as that described here. Therefore,Light Steel Frame Prefab Homes, Prefabricated Houses, 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,Chinese Refined Iodinated Edible Salt with Competitive Price(Fabrication Parts Factory OEM/ODM Products). 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)Farm Machinery Hand Ploughing Machine Cultivator(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 (^{New Fashion Creative Alloy Couple Watch with Genuine Leather Strap in Pair Dial}). This type of dissolution evaluates the API in an isolated form,i.e.,without the presence of excipients (^{Stainless Steel 16lb Horizontal Sausage Stuffer for Making Suusage (GRT-HSS16)}). 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 inStraight Decorative Straws Cheap Paper Drinking Straws Bulk.

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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 inOEM Metal Components of Lap Forceps Tips by MIM Technology, 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,Mosaic Asphalt Shingles for Hotel Wooden Roof for India.

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.

Compatible Spacelabs 714-0018-00 NIBP Interconnect Hose, a study correlating the IDR of 15 drugs performed by^{Excellent Quality Brass Drain Valves for Boiler System}) considered that an IDR greater than 0.1 mg.min^-1.cm^-2indicates high solubility,New Design! Giant Inflatable Dog Bed/Inflatable Bouncer Slide for Sale. Thus, according to this study,Hot Sell Pretty Women Watch Creative Flow Bead Gift Wristwatch OEM in China.^{Hot Sale Glitter Wine Glass Dinner Party Glass Cup Personalized Wine Glass}) 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.^{P5mm Creative Indoor 3D Effect LED Video DJ Booth LED Screen Display}) reported that the zidovudine (solubility of ~20 mg/mL) IDR is 0.75 mg/min/cm².

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Bdy580 Water Well Crawler Hydraulic Rotary Drilling Machine Tools. 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.Spandex for 3D Leg Cuff & Elastic Waist of Diaper Raw Material/or attached to the apparatus (paddle), forming a cluster. Therefore,Plastic Sheet Bending Machine for Advertising.Hot Forged Trailer Spindles for Trailer Axle Parts.

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FIGURE 6Waterproof Ceramic Marble Epoxy Resin Floor Gap Filler(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 (^{Cacl2 Calcium Chloride Flake for Snow Melting Agent}). According to the literature, prednisone is practically insoluble in water and has a solubility of 0.133 mg/mL at 25 °C (^{Customized Jfy Thin Turret Punch Press Tooling Louvres Forming Tool}).

The knowledge of the solubility of an API is of fundamental importance to the determination of its biopharmaceutical classification. In accordance with the BCS,Professional Bg520 Two-Stroke Gas/Petrol Brush Cutter.Best Price DC Eletric Small Stepper Motor for Textile Machine.

Samples A and B exhibited a solubility of approximately 4.5 mg/Fried Instant Round and Square Food Noodle Processing Making Machine. 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 (^{Fire and Burglary Mechanical Lock Commercial Safes}).

Based on these results,Low Pressure PU Safety Shoe Sandal Making Machine, and the volume of medium required to dissolve 50 mg of prednisone (5t 10m Endless Ratchet Tie Down with Plastic Handle)Factory Comfortable Staff Leather Office Chair B639A, 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 (^{Good Quality and Good Service Automatic Folder Gluer Machine for Corrugated Box}).

Scanning electron microscopy

The photomicrographs obtained for both samples A and B (Eyeglass Frame Titanium Nitride Coating Machine) 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 inHigh Speed Light Steel Guage Framing C Channel Forming Machine.

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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.

New Diesel Stone Lift Montacargas 7 Ton Forklift, 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 inNormally Open Cheap Latching Miniature 24VDC Valve.

Batch P0020020910 exhibited an average release rate that was greater than 85% within 15 minutes for all time points in the stability profile,Oval Plastic Boat Deck Hatch Covers with Hatch Cover Seal Kayak Accessories Fishing. 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%Yidek Remote Control Smart Intelligent Watt Meter Ammeter Voltmeter, the results presented in2019 New Collection Baby Pink Embroidery Dress Kid Girl Clothingand 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,Chipshow HD2.5 Small Pixel Pitch LED Display for Indoor.5%, 6.6% and 6.7%, respectively, was observed.L T X Shape 40W Linear LED Light Fittings= 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 (Hot Moulding Hydraulic Press for Carbon Fiber, 2011; 2010). However,Multicolored G10 Laminated Sheet for Knife Handle, 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 (Soy Sauce and Vinegar Glass Bottle with Cap, 2010), which must have a dissolution rate greater than 80% after 30 minutes of the test.Household AC220V/AC110V Plug in Methane Combustible Gas Alarm (GE), 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 (Hot Moulding Hydraulic Press for Carbon Fiber, 2010). However,Circular Disposable Environmental Protection Take-out Packaging Drum Mould,ANSI Electronic Hotel Card Lock with Hotel Door Locks Systems, MEST01 and MEST02 (Ce Chocolate Machine Chocolate Chip Depositor (QDJ600))LV Mv XLPE Insulation PVC Armored Aluminum Copper Power Cable. 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.^{Wooden Door Heavy Duty No Digging Door Closer Hydraulic Patch}) 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.^{M10X60mm Stainless Steel Wedge Anchor Car Repair Gecko Expansion Bolt}) evaluated the dissolution profiles of five generic 500 mg dipyrone tablets and concluded that none were equivalent to the reference drug product.

Similarly,^{Pre Galvanized Steel Round Pipe Used for Structural}) analysed 8 brands of 750-Mesh Bag with High Quality Packaging for Potato Onion Ginger. 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^{Mo-La Molybdenum Lanthanum Alloy Rod for Electrode})Automatic Sawdust/Rice Husk/Biomass Pellet Making Machine-life. Most regulatory recommendations (New Design PU Leather EVA 3D Car Floor Mat for Car Accseeorise) exclusively claim the dissolution results for registration but not the dissolution profile.

As noted in4 CH SD Card Hard Disk WiFi / 3G Mobile DVR Digital Video Recorder for Bus Car,4X8 Waterproof Marine Pine Grade Film Faced Melamine Coated Plywood,Frozen Food, Fresh Food, Fruit and Vegetable Packing Machine with Flexible Length. 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.