Pre-formulation studies

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PREFORMULATION STUDIES IN PHARMACEUTICAL PRODUCT DEVELOPMENT Mr. Sagar L. Vekariya M.Pharm (pharmaceutics) BABARIA INSTITUTE OF PHARMACY, VARNAMA, VADODARA

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INTRODUCTION According to the Product Quality Research Division of the US Food and Drug Administration (FDA), the goal of pre-formulation is to: investigate critical physicochemical factors which assure: - identity, - purity of drug substances, - formulatability, - product performance - and quality. Significance in Formulation development It can be defined as an investigation of physical and chemical properties of a drug substance - alone and when combined with excipients for: Dosage Form selection, rationalization and Formulation design Stable dosage form development and Optimization Understanding the underlying process controlling principles Bioavailable dosage form development Efficient Process monitoring control, validation, and continuous improvement Determination of processes susceptible to failure upon scale-up Efficient mass-production (Technology transfer and scale up) Reducing regulatory issues and getting confidence and relief Showing value of workmanship to company management

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Preliminary Data taken into consideration, (that sets link from discovery of New Chemical entity with early development, process scale-up and manufacturing of final dosage form, useful in guiding, and becoming part of, the main body of preformulation work) physicochemical data: chemical structure, different salts available gross particle size, melting point, infrared analysis: FTIR chromatographic purity: HPLC, UPLC characterizations of different laboratory-scale batches. therapeutic class of the compound and anticipated dose supply situation the development schedule (i.e., the time available) Preformulation studies effecting Dosage Form Considerations aqueous and non-aqueous solubility irritability of drug and its solution storage and handling requirements for the dosage form shelf life desired rate of entry of actives to desired body tissues desired onset of action stability of drug at the site of administration patient acceptance by the customary routes for the defined class

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DATA GENERATED BY PRE-FORMULATION STUDIES

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DATA GENERATED BY PRE-FORMULATION STUDIES

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DATA GENERATED BY PRE-FORMULATION STUDIES

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DATA GENERATED BY PRE-FORMULATION STUDIES

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METHODS IN PREFORMULATION SCREENING CheqSol software Much faster than shake-flask methods to Measure equilibrium and the turbidimetric (or kinetic) solubilities in the same experiment Provides insights into compound behavior that will be of value for the better understanding of drug bioavailability, modeling of precipitation processes, and for investigating changes of crystalline form in suspensions. Solubility studies are required for any drug molecules during drug discovery, as well as in confirmation of bioavailability issues, human formulation design, and Biopharmaceutical Classification, which is required by the FDA. Processes data, and controls Sirius’ existing GLpKa, PCA200, and D-PAS instrumentation. CheqSol works by monitoring the pH, as hydrochloric acid (HCl) or potassium hydroxide (KOH) solutions are carefully added to a 10-mL solution of the ionized drug until it precipitates, as detected by an abrupt decrease in the amount of light transmitted through the solution. The concentration at this point is equivalent to a kinetic solubility. Chasing equilibrium then begins—HCl and KOH are added sequentially to force the solution to become supersaturated or subsaturated, and the state of saturation is determined from subsequent small changes in the pH reading. The concentration of unionized species at the crossing points, when the pH change is zero and the sample is neither super nor subsaturated, is equal to the intrinsic solubility.

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SPECTROSCOPIC AND MICROSCOPIC ANALYSIS Energy dispersive X-ray spectrometry (EDS) for quick and easy elemental analysis of samples in the SEM. Minimum detection limit of 0.1% by weight. Wavelength dispersive X-ray spectrometry (WDS) Detailed elemental analysis of samples in the SEM. JEOL Four-Crystal Spectrometer attached to the JSM-35C SEM can be used for 1-mm spot analysis, digital and analog line scans, and X-ray image mapping, elements detection from Be to U, minimum detection limit of 0.01% by weight, fully quantitative results. Inductively Coupled Plasma-atomic emission spectroscopy (ICP-AES) provides trace level and bulk elemental analyses of solid and liquid samples. Using Varian Analytical Instruments Liberty 100 air pass inductively coupled plasma atomic emission sequential spectrometer, minimum detection limits better than 1 ppb by weight (element/line dependent) bulk solid acid digestion (for powders, residue, and so on) and liquid analyses can be performed. Analysis of all elements from Li to U (excluding N, O, F, S, and noble gases), 0.75-m Czerny Turner monochromator with holographic grating allows high intensity spectra up to four peak orders with 0.006-nm resolution through a wavelength range of 189–900 nm.

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Surface analysis (AES/XPS) Electron spectroscopy for elemental analysis of surfaces, sensitive to as low as two atomic layers. Physical electronics model PHI-570 Auger Electron Spectroscopy/X-ray Photoelectron Spectroscopy System is a double pass cylindrical mirror energy analyzer with dual anode (Mg/Al) X-ray source and has a rapid sample introduction probe. It can detect elements at the first five to ten atomic layers of sample and detect all elements except H and He. Scanning electron microscopy for high resolution and high magnification photographs. Perform elemental analysis with EDS and WDS attachments e.g. JEOL JSM6320F & JSM-35C research-grade SEM can provide imaging from 10 to 400,000. Very high magnification images with excellent depth of focus can be obtained. Important when rough surface structures are being examined. Information about the chemical composition at the microlevel and the phase composition of the sample under study can be directly obtained. Using SEM, such as the Fraunhofer Institut Fu¨ r Fertigungstechnik undAngewandte Material for Schung it is possible to magnify structures up to 500,000 times with high depth of focus. A finely focused electron beam allows structures down to 0.001 mm to be resolved. The acceleration voltage of the electron beam directed at the sample surface can be varied between 300 V and 30 kV. The emitted secondary and back-scattered electrons give information about the topology of the sample. Back-scattering electrons can also be used to produce material contrast images.

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THERMAL ANALYSIS Determine calorimetric and mechanical properties, such as heat capacity, mechanical modulus, sample mass, and dimensional changes in temperature ranges between -150 C and 1600C. Utilizes DSC, TGA, TMA, and dynamic mechanical analysis instrumentation supplemented by software products, accessories, consumables, and documentation. Applications are frequently found in research and QC environments. Covers Characterization of materials, process development, and evaluation as well as safety investigations. The associated METTLER TOLEDO FP900 series includes instruments for the several measuring cells for the determination of various thermal values and TOA applications as Physical properties: such as melting, boiling, Investigate the melting range of transparent and non-transparent substances and their Crystallinity. Investigation of crystal melting, polymorphism and liquid crystal transitions. dropping, or softening points of fats, resins and bitumen determination of cloud and clear point Cloud and clear points characterize nonionic surfactants (tensides), has a hot stage for thermal microscopy and measurement of light transmission. (The hot stage can be equipped with a microscope or a photomonitor and allows the optical investigation of crystals and amorphous substances during phase transitions.

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DSC (Differential Scanning Calorimetry) Measures the amount of energy (as heat) absorbed or released as a sample is heated, cooled, or held at constant temperature. A well designed and properly replicated DSC profile would yield such as physical properties as melting (endothermic), solid-state transitions (endothermic), glass transitions, crystallization (endothermic), decomposition (exothermic) and dehydration or desolvation (endothermic) purity (of high purity compounds. When the sample is heated, inorganic salts first split off their water of crystallization, and then other volatile components evaporate. The weight loss indicates the amount of water or volatile components in the sample. TGA (Thermogravimetric Analysis) The amount of weight lost on heating a sample. It is based on a sensitive balance that records the weight of the sample (generally 5–10 mg) as it is heated under nitrogen. Helps formulators to understand decomposition behavior. Some similar information can be obtained with the vapor sorption analyzer, Allows users to measure effects at much higher temperatures. Even set the starting and ending temperatures and control the speed at which the temperature rises or falls. can detect the presence of water or solvent in different locations in the crystal lattice. Has an advantage over a Karl Fischer titration or a loss on drying experiment that can only detect the total amount of moisture present. Requires smaller quantities of the compounds than the other two techniques.

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Dynamic Vapor Sorption (DVS) Technique Introduced in 1994 revolutionized the world of gravimetric moisture sorption measurement Replaced time- and labor-intensive desiccators into the modern world of cutting-edge instrumentation and overnight vapor sorption isotherms. Resolution: down to 0.1 mg, a 1% change in the mass of a 10-mg sample on exposure to the humidity-controlled gas flow is both easily discernable and reproducible. Show percent mass increases, but often a hysteresis loop relationship is observed, where there is crystallization of compound that results in the expelling of excess moisture. DVS is a useful study when amorphous forms are involved upon size reduction in a very low level of amorphous character that cannot be detected by techniques, such as XRPD; microcalorimetry etc. Can detect 10% amorphous content (the limit of detection is 1% or less). The amorphous content of a micronized drug can be determined by measuring the heat output caused by the water vapor inducing the crystallization of the amorphous regions. Studies: polymorphism, compound stability, bulk and surface adsorption effects of water and organic vapors. Formulations: as dry powder inhaler devices, as it can cause agglomeration of the powders and variable flow properties.

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Isothermal Microcalorimetry Can also be used to determine hygroscopicity of substances. In the ramp mode, this technique can be used, like DVS, to examine milligram quantities of compound. This instrument utilizes a perfusion attachment with a precision flow switching valve. The moist gas is pumped into a reaction ampoule through two inlets, one that delivers dry nitrogen at 0% RH and the other that delivers nitrogen that has been saturated by passing it through two humidifier chambers maintained at 100% RH. The required RH is then achieved by the switching valve, which varies the proportion of dry to saturated gas. The RH can then be increased or decreased to determine the effect of moisture on the physico-chemical properties of the compound. It is probably more popular to perform microcalorimetry in the static mode. In the so-called internal hygrostat method, the compound under investigation is sealed into a vial with a sealed pipette tip containing the saturated salt solution chosen to give the required RH. Microthermal analysis A recently introduced Thermo-analytical technique Combines the principles of Scanning Probe Microscopy with thermal analysis via replacement of the Probe tip with a Thermistor. Allows samples to be spatially scanned in terms of both topography and thermal conductivity, whereby placing the probe on a specific region of a sample and heating, it is possible to perform localized thermal analysis experiments on those regions.

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Molecular Spectroscopy Foundations for fluorescence correlation spectroscopy (FCS) laid in the early 1970s, Widely used when single molecule detection was established almost 20 years later with the use of diffraction-limited-confocal volume element. The analysis of molecular noise from the GHz- to the Hz-region facilitates measurements over a large dynamic range covering photophysics, conformational transitions and interactions as well as transport properties of fluorescent biomolecules. From the Poissonian nature of the noise spectrum the absolute number of molecules is obtainable. Originally used for the analysis of molecular interactions in solutions, The strength of FCS lies also in its applicability to molecular processes at either the surface or interior of single cells. Examples of the analysis of surface kinetics including on and off rates of ligand–receptor interactions will be given. The possibility of obtaining this type of information by FCS will be of particular interest for cell-based drug screening.

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Infrared spectroscopy Differentiates solid-state structures of compounds just as well as it differentiates and identifies the chemical structures and peculiarities. For identifying organic and inorganic compounds by comparison with library references. Can be used to distinguish the polymorphic forms of a compound. The presence of solvent or water can be detected using this technique as a result of the broad OH stretch associated with water. The IR is applied to studies in a number of ways: by Nujol mull, KBr disc, or the diffuse reflectance (DR) technique. Compression can be a disadvantage if the compound undergoes a polymorphic transformation under pressure. The standard IR spectrum is calculated from the Fourier-transformed interferogram, giving a spectrum in percent transmittance (%T) versus light frequency (cm-1). e.g. Perkin Elmer System 2000 offers near IR, mid IR, far IR: 15,000–15,030 cm, transmittance (T), specular reflectance and diffuse reflectance (DR), horizontal and vertical attenuated total reflectance (ATR) microscope (0.10-mm spot, 10,000–10,580 cm). Near-infrared (NIR) spectroscopy An important technique for pharmaceutical analysis. This spectroscopy is simple and easy because no sample preparation is required and samples are not destroyed. In the pharmaceutical industry, NIR spectroscopy has been used to determine several pharmaceutical properties, and a growing literature exists in this area.

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X-Ray Powder Diffraction (XRPD) X-rays are electromagnetic radiation of wavelength about 1A ° (10210 m), which is about the same size as an atom. They occur in that portion of the electromagnetic spectrum between gamma rays and the ultraviolet. Enabled to probe crystalline structure at the atomic level. X-ray diffraction has been in use in two main areas: for the fingerprint characterization of crystalline materials and the determination of their structure. Each crystalline solid has its unique characteristic X-ray powder pattern, which may be used as a “fingerprint” for its identification. For Identified materials crystallography: may be used to determine its structure, that is, how the atoms pack together in the crystalline state and what the interatomic distance and angle are. Most important characterization tools used in solid-state chemistry and materials science. The size and the shape of the unit cell for any compound can be most easily determined using the diffraction of X-rays. To estimate the average shape and “habit” of organic crystalline material using a single crystal. The relative intensities of the peaks in an XRPD pattern from a sample exhibiting a “standard” preferred orientation correlates with the shape of the crystallites present. for phase analysis, crystallographic information, Residual stress, texture analysis, Reflectometry on powders, bulk, or thin films. e.g. Philips X’Pert PRO, and a second Philips dual diffractometer system with automated PC control, independent sample spinner, and sample changer can be used for crystallography and Rietveld analysis of samples; flat, irregular, thin films, or in glass capillaries

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Dissolution Testing Is a significant factor involved in drug bioavailability. Two stages process: salvation of the solute molecules by the solvent molecules, followed by transport of these molecules from the interface into the bulk medium by convection or diffusion. Factors effecting: aqueous solubility of the compound; particle size, crystalline state (polymorphs, hydrates), pH, and buffer concentration can affect the rate. physical properties: such as viscosity and wettability depend on the rotation speed. Dissolution should simulate in vivo conditions: be carried out in a large volume of dissolution medium, or there must be some mechanism whereby the dissolution medium is constantly replenished by fresh solvent. USP paddle dissolution apparatus is mandatory when developing a tablet, The rotating disc method has great utility with regard to preformulation studies. Intrinsic dissolution rate is the dissolution rate of the compound under the condition of constant surface area. The rationale for the use of a compressed disc of pure material is that the intrinsic tendency of the test material to dissolve can be evaluated without formulation excipients.

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Dissolution Testing (contd) analytical techniques to follow the dissolution process; UV-visible spectrophotometry, and HPLC with fixed or variable wavelength detectors (or diode array) The UV system employs a flow through system and does not require much attention; however, if HPLC is used, then any aliquot taken should be replaced by an equal amount of solvent. The intrinsic dissolution rate is given by the slope of the linear portion of the concentration versus time curve divided by the area of the disc and has the units of mg/min cm2. USP has 7 different apparatus most tablets and capsules use Apparatus 1 or 2 also known as Basket and Paddle USP dissolution apparatus 3 (reciprocating cylinder) it requires much less water and considerably fewer chemicals. Flow-through cell (apparatus 4):sink conditions can be maintained, whatever the drug solubility, using an open loop, In a closed-loop mode, in which a small volume of medium circulates through the system to provide sample concentration levels sufficient for the assay. Apparatus 5 (paddle over disk): SS disk for holding Transdermal system at the bottom of vessel with release surface parallel with the bottom of paddle blade. Apparatus 6 (rotating cylinder), USP Apparatus 7 (Reciprocating Holder): assembly consists of a set of volumetrically calibrated or tared solution containers made of glass or other suitable inert material, a motor and drive assembly to reciprocate the system vertically and to index the system horizontally to a different row of vessels automatically, if desired, and a set of suitable sample holders. The solution containers are partially immersed in a suitable water bath of any convenient size that permits maintaining the temperature.

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Liquid Chromatography To assess the degradation compounds in testing the stability of new drugs since in these studies the identification of degradation products is very important. Combined with mass spectrometer and the newer instrumentation, liquid chromatography/tandem mass spectroscopy (LC/MS/MS), and so on, offer powerful tools for the elucidation of degradation mechanism. Isocratic elution is often the most desirable method as it does not require post-equilibration phase for the next analysis required for studying interaction for a matrix of factors and excipients Gradient elution offers the advantage of sharper peaks, increased sensitivity, greater peak capacity, and selectivity (increased resolving power). Detector to be used is usually dictated by the chemical structure of the compound under investigations. As most compounds of pharmaceutical interest contain aromatic rings, UV detection is the most common detection method. The most appropriate wavelength is selected from the UV spectrum of the pure compound and that of the system suitability sample. Other detection include refractive index, fluorescence, or mass selective detectors.

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Inverse gas chromatography (IGC) Principles of IGC are very simple, being the reverse of a conventional gas chromatographic (GC), the stationary phase is the powder under investigation. A cylindrical column is uniformly packed with the solid material of interest, typically a powder, fiber, or film. A pulse or constant concentration of gas is then injected down the column at a fixed carrier gas flow rate, and the time taken for the pulse or concentration front to elute down the column is measured. Standard instrument configuration: have thermal conductivity detector (TCD) and a flame ionization detector (FID), mass spectrometer (as per customer requirements). IGC is an alternative technique where the powder surface is characterized by the retention behavior of minute quantities of well-characterized vapors that are injected into a column containing the material of interest, Allows: differentiation between the moisture and the organic solvent elutants. Behavior of pharmaceutical solids, during either processing or use, can be noticeably affected by the surface energetics of the constituent particles. Linking surface energetic data with triboelectric charging is helpful for studying the effect of surface moisture on surface energetics. Molecular modeling has also recently been used to explore the links between IGC data and the structural and chemical factors that influence the surface properties, thereby achieving predictive knowledge regarding powder behavior during processing. IGC is a gas phase technique for characterizing surface and bulk properties of solid materials. Used for characterization of particulates, fibers, and thin films for sorption solutions. Applications: surface energetics, heat of sorption, sorption isotherms, phase transitions, diffusion kinetics,

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Particle Size Distribution Particle size reduction particularly mandates the study of particle size distribution studies using techniques: as sieving, optical microscopy in conjunction with image analysis, electron microscopy, Centrifugal particle size analyser sedimentation rate based the Coulter counter and laser diffractometers, Selection based on depending on the anticipated size of the particles. Size characterization is simple for spherical particles, the study of irregular particles requires specialized methods. Laser Diffraction Instrument measures particle size by laser diffraction. Based on: light scattered through various angles, which is directly related to the diameter of the particle By measuring the angles and intensity of scattered light from the particles, a particle size distribution is obtained. Particle diameters reported are the same as those produced by spherical particles under similar conditions. Each particle is treated as spherical and essentially opaque to the impinging laser light.

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Laser Diffraction studies Two different light scattering (DLS) methodologies can be used to characterize particles. The classical, “static” or “Rayleigh” scattering or multiple angle laser light scattering, provides a direct measure of mass. The DLS, which is also known as “photon correlation spectroscopy” (PCS) or “quasi-elastic light-scattering” (QELS), uses the scattered light to measure the rate of diffusion of the particles. This motion data is conventionally processed to derive a size distribution for the sample, where the size is given by the “Stokes radius” or “hydrodynamic radius” of the protein particle. This hydrodynamic size depends on both mass and shape (conformation). Dynamic scattering is particularly good at sensing the presence of very small amounts of aggregated particles and studying samples containing a very large range of masses. Can be quite valuable for comparing the stability of different formulations, including real-time monitoring of changes at elevated temperatures. For submicron materials, particularly colloidal particles, QELS is the preferred technique. Two theories: Fraunhofer theory: the particles are spherical, nonporous, and opaque; diameter is greater than wavelength, particles are distant enough from each other, have random motion, and all the particles diffract the light with the same efficiency, regardless of size and shape. The Mie theory takes into account the differences in refractive indices between the particles and the suspending medium.

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If the diameter of the particles is above 10 microns: then the size produced by utilizing each theory is essentially the same. Discrepancies may occur when the diameter of the particles approaches that of the wavelength of the laser source. The following are the values reported from diffraction experiments: D (v, 0.1) is the size of particles for which 10% of the sample is below this size. D (v, 0.5) is the volume (v) median diameter, of which 50% of the sample is below and above D (v, 0.9) is the size of the particle for which 90% of the sample is below this size. Mastersizer 2000, Malvern Engineered and optimized the system according to the physics of light scattering Mie scattering model. During the laser diffraction measurement, particles are passed through a focused laser beam. These particles scatter light at an angle that is inversely proportional to their size The angular intensity of the scattered light is then measured by a series of photosensitive detectors. The number and positioning of these detectors in the Mastersizer 2000 has been optimized to achieve maximum resolution across a broad range of sizes. The map of scattering intensity versus angle is the primary source of information used to calculate the particle size. Allow accurate sizing across the widest possible dynamic range. Increased sub-micron resolution is delivered via the patented dual-wavelength detection system. A short wavelength blue light source is used in conjunction with forward and backscatter detection for enhanced sizing performance combined with red-light measurements, for superior sensitivity across a wide size range.

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Malvern Zetasizer Non-invasive back scatter (NIBS®) technology used for particle sizing: extends the range of sizes and concentrations of samples that can be measured can detect the scattering information at 173°. (backscatter detection). Sensitivity in the 0.6nm to 8.9 micron range. for the accurate, reliable and repeatable size analysis of particles and molecules in solution. — Little or no dilution necessary — Colloid size and size distribution — Pharmaceuticals — Nanoparticles — Emulsions Highest ever sensitivity, accuracy and resolution for the measurement of zeta potential. a combination of Laser Doppler Velocimetry and Phase Analysis Light Scattering (PALS) in Malvern’s patented M3-PALS technique. For samples of very low-mobility also, Zeta potential and mobility distributions can be calculated. By static light scattering (SLS) and the classical Debye plot, the molecular weight of random coiled polymers up to 5 x 105 Da as well as globular polymers and proteins up to 2 x 107 Da can be determined without the necessity for multi-angle measurements for: — Protein crystal screening — Oligomer identification — Protein-melting point

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Further data generated in Pre-formulation studies for the dosage form Includes: • Stability data: – chemical stability, accelerated and stress studies – thermal properties – hygroscopicity (storage conditions) – Photochemical stability – excipients and packaging compatibility studies; • early stage formulation: – design composition and form according to specifications, dose and bioavailability. Depending on phase development, amount of drug available, the above pre-formulation studies will be adapted to obtain the right level of information according to the risk that the customer is ready to take.

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COMPATIBILITY STUDIES Compatibility studies are conducted to accelerate the development of formulations by allowing formulators to eliminate those excipients that cause API degradation. Factors effecting compatibility between drugs and potential formulation aids: include local pH and water content, which affect the chemical stability of the API. Incompatibilities: arise because of either intrinsic degradation of the API, is facilitated by the excipients or a covalent chemical reaction between the API and the excipients. Instrumental methods: Using HPLC, DSC, FTIR (Fourier transform infra-red), or TGA Using DSC alone is not recommended since it can throw up false negatives and positives, need to be supported by other techniques such as FTIR and HPLC. Microthermal analytical technologies: localized thermomechanical analysis (L-TMA), localized differential thermal analysis (L-DTA), nanosampling, thermally assisted particle manipulation (TAPM), and photothermal microspectrometry (PTMS), specialized techniques not widely available in industry at this point in time. Methods for the evaluation of solid-state stability and compatibility between drugs and excipients: isothermally and non-isothermally, viz. suspension, storage of powders, and compacts at specified humidities and elevated temperatures, dependent on type of dosage form selected. HPLC, method (which requires a specific, quantitative assay method, for example, for either test substance or its degradation products) was preferred for its accuracy over DSC in compatibility testing. gave quantitative information. Disadvantages of the HPLC system: compared with DSC the tests tend to consume more compound than the DSC test and are conducted over longer storage times, one to two months at 60degC to 80degC. DSC may be used to predict that interactions may occur

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SOLID DOSAGE FORM CONSIDERATIONS Characteristics Most pharmaceutical are either tablet or capsule for a variety of safety, cost, and marketing considerations. This is a default dosage form unless it is predetermined in the case of therapeutic proteins or other drugs that must be administered by parenteral route or other specific routes for specificity of the desired activity . Typical parameter studies: ability of a powder mix to flow well in manufacturing machines, intrinsic characteristics that make it compressible. Properties studied include crystal structures (polymorphs), external shapes (habits), compression properties, cohesion, powder flow, micromeretics, crystallization, yield strengths effects of moisture and hygroscopicity, particle size, true bulk and tapped density, surface area. Porosity: pore-size and its distribution, %porosity and specific pore volume, bulk density

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SOLUTION FORMULATIONS Development of a solution formulation requires a number of key pieces of preformulation information Include: aqueous solution, emulsion, microemulsion, liposomes, nanoparticles etc Most important: Solubility (and any pH dependence), stability, sterility Solubility consideration pH Manipulation Cosolvents Emulsion Formulations: particle size zeta potential, Method/instrument of manufacture, Physical instability of emulsions can take a number of forms, for example, creaming, flocculation, coalescence, or breaking, while chemical instability can be due to hydrolysis of the stabilizing moieties. Microemulsions A way of solubilizing drugs for intravenous delivery: thermodynamically stable, complex dispersions consisting of micro domains of oil and water, which are stabilized by alternating films of surfactants and co-surfactants. The droplet size of microemulsions is generally less than 150 nm. One feature of microemulsions is that they are clear in contrast to the milk-like appearance of the conventional emulsions.

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Stability Considerations The stability of pharmaceuticals, from a regulatory point of view, is usually determined by forced degradation studies. These studies provide data on the identity of degradants, degradation pathways, and the fundamental stability of the molecule. Terminal sterilization aspects: stability under autoclaving or perform aseptic processing and sterile filtration Acceptable reasons for not proceeding with a terminally sterilized product are: pH changes, color changes, carbonate buffering loss, container closure problems, and drug or excipient degradation. Sterility Consideration For parenteral formulations, a sterile solution of the compound is required. To assess the stability of the emulsion, heating and freezing cycles as well as centrifugation can be employed Most parenteral products on sale worldwide are multi-dose formulations, which require the inclusion of an antimicrobial preservative. Preservatives: benzyl alcohol, chlorobutanol, m-cresol, phenol, phenoxyethanol, propylparaben, and thiomersal. Of these, benzyl alcohol and combinations of methyl and propylparaben are the most popular

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Effect of Metal Ions and Oxygen on Stability After hydrolysis, oxidation is the next most important way by which a drug can decompose in both the solid and liquid states. It is a complex process that can take place by way of such mechanisms as autoxidation, nucleophilic or electrophilic additions, and electron transfer reactions Use of Chelating agents: Ethlenediaminetetraacetic Acid and Chelating Agents the various salts of ethylenediaminetetraacetic acid (EDTA), hydroxyethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentacetic acid (DPTA), and nitrilotriacetate (NTA) Osmolality Body fluids, such as blood, normally have an osmotic pressure, corresponding to that of a 0.9% w/v solution of sodium chloride, or 5.0% dextrose Osmotic pressure lower than 0.9% w/v NaCl are known as hypotonic, and those with osmotic pressure greater than this value are said to be hypertonic. The commonly used unit to express osmolality is osmol, and this is defined as the weight in grams per solute, existing in a solution as molecules, ions, macromolecules, etc., that is osmotically equivalent to the gram molecular weight of an ideally behaving nonelectrolyte. Important in the parenterals and ophthalmic field, Formulations are directed to avoid the side effects or finding methods of administration to minimize them. Determinations: using osmometer by freezing point depression principles

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FREEZE-DRIED FORMULATIONS Unstable drug solution: an alternative formulation approach will be freeze-drying to produce the requisite stability. Prerequisite: enough aqueous solubility and stability over the time course of the process Compound is unstable in water: alternative solvent such as t-butanol Preformulation studies can be performed to evaluate this approach and to aid the development of the freeze-drying cycle. Three main stages: (i) freezing of the solution, (ii) primary drying, and (iii) secondary drying Inclusion of excipients is necessary as bulking agents and/or stabilizing agents. Production conditions should ensure that the process is efficient producing a stable product Freezing and heating behavior of solutions containing the candidate drug studied: DSC and freeze-drying microscopy Importance of glass transition of frozen solution formulation as freeze-drying an amorphous system above this temperature can lead to a decrease in viscous flow of the solute (due to a decrease in viscosity) after the removal of the ice. This leads to what is commonly known as “collapse”, and for successful freeze-drying, it should be performed below the Tg. Consequences of collapse: high residual water content and prolonged reconstitution times and increase in the mobility of molecules above the Tg may lead to in-process degradation

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If the drug substance is not soluble, then the compound may be administered as a suspension. Used for oral administration of drugs to animals for safety studies, for early-phase clinical studies in humans, or for the intended commercial dosage form, for example, ophthalmic, nasal, oral, etc. Important data for suspensions at the preformulation stage: Solubility, Particle size, and Propensity for crystal growth Chemical stability. Furthermore, during development, it will be important to have knowledge of the viscosity of the vehicle to obtain information with respect to settling of the suspended particles, syringibility, and physical stability Successful suspension: insolubility of the candidate drug as large hydrophobic drugs like steroids, Problematic for: weak acids or bases showing appreciable solubility. Remedy: reducing the solubility by salt formation eg. a calcium salt of a weak acid may be sufficiently insoluble for a suspension formulation. Difficulties because of hydrate formation causing a concomitant crystal growth, which need to be prevented by using different excipients. Crystal growth by Otswald ripening : not attributable to a phase change It is the result of the difference in solubility between small and large crystals. promoted by temperature changes during storage, particularly if there is a strong temperature-solubility relationship, as the temperature increases, the small particles of the drug will dissolve, which is followed by crystal growth as the temperature decreases CONSIDERATIONS FOR SUSPENSION FORMULATION

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TOPICAL/TRANSDERMAL FORMULATIONS Offers several potential advantages compared with the oral route: avoidance of fluctuating blood levels, no first-pass metabolism, and no degradation attributable to stomach acid. However, the transdermal route is limited because of the very effective barrier function of the skin as Large, polar molecules do not penetrate the stratum corneum well. Physicochemical properties of candidate drugs Intrinsic properties of the molecule: include molecular weight and volume, aqueous solubility, melting point, and log P. pH will have an influence on their permeation: since many compounds are weak acids or bases: transport of zwitterionic drugs though skin has been enhanced was to form a salt. Vehicles: creams, ointments, lotions, and gels. Solubility of the compound in the vehicle needs to be determined. Problems: Crystal growth if the system is supersaturated Chemical and physical stability also needs to be considered (e.g. degradation of this compound occurred in an aqueous phase or compartment that was undisturbed by the oily cream excipients, decomposes because of oxidation, then an antioxidant may have to be incorporated.

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Investigation of Physical structure of creams: DSC, TGA, microscopy, reflectance measure, rheology, Raman spectroscopy, and dielectric analysis eg: TGA as quality-control tool : there were two peaks in the derivative curve of aqueous creams attributable to the loss of free and lamellar water. Small-angle X-ray measurements: for the lamellar structure of creams Laser diffraction method: measure particle size of drugs dispersed in ointments, small particle size was required to ensure efficacy of the drug as size of the particles was especially important if the ointment was for ophthalmic use where particles must be less than 25 microns, laser diffraction offers a more rapid analysis

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INHALATION DOSAGE FORMS (Pressurized MDI) LUNGS or Pulmonary delivery: Large surface area available, drug delivery via the lung has a number of advantages over the oral route since the rate of absorption of small molecules from the lung is only bettered by the intravenous route. The bioavailability is usually higher than that obtained from drug delivery by the oral route. Particularly true for hydrophobic compounds, which can show extremely rapid absorption Optimum Particle size: Problematic and requires the drug to be reduced in size to between 2 and 6 mm for optimal effect, size greater than 6 mm, the compound is deposited in the mouth and esophageal region, so no clinical effect apart from the part that is swallowed. Particles of size 2 mm, on the other hand, are deposited in the peripheral airways/alveoli. Particle size is reduced by micronization to particles of approximately 1 to 6 mm, which are capable of penetrating the deep airways and impact at the site of action, can cause problems because of the reduction in crystallinity and poor flow properties as a result of the milling process. The effect of micronization on samples can be assessed by variety of techniques, for example, DVS, microcalorimetry, and IGC. Formulated as a suspension or as a solution depending on the solubility of the drug in the propellant (or the addition of a cosolvent). Addition of other terms such as log P, molar volume, molecular weight, etc., although suspensions offer the advantage of superior chemical stability, they may have problematic physical stability in terms of crystal growth or poor dispersion properties. Choice of Propellant: Surfactants and polymers used as suspension stabilizers in CFC formulations are not soluble enough in the HFAs to be effective, needs proper selection of surfactants and polymers existence of solvate by DSC, TGA, hot-stage microscopy, XRPD, and infrared spectroscopy, and compatibility of the propellants with the valve elastomers

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Dry Powder Inhalers DPIs do not rely on the CFC or HFA propellant gases and are hence more “environmentally-friendly” than MDIs. There are a number of devices that can deliver drugs to the lung as dry powders, for example, TurbuhalerTM and DiskhalerTM. DPIs rely on a larger carrier particle such as a-lactose monohydrate to which the drug is attached. (The lactose is usually fractionated such that it lies in the size range 63–90 mm.) On delivery, the drug detaches from the lactose, and because the drug is micronized, it is delivered to the lung, whereas the lactose is swallowed. The use of alternative carriers, such as erythitol, mannitol, and trehalose For restoring the crystallinity is to condition the surface of the micronized drug by exposing it to elevated relative humidities or organic vapors. The net effect of this procedure is to crystallize the amorphous regions, making the powder better suited for formulation in a DPI. Crystallization from supercritical fluids as a method for producing micronized particles for inhalation Using DVS, AFM, and twin-stage impinger data, showed effects of increased humidities, the fine-particle fraction for both samples decreased because of the amorphous character induced by the micronization process: the crystallization of the amorphous regions due to the elevated humidity causes the particles to fuse to the lactose carrier. Performance of DPIs is governed by a number of factors such as van der Waals, electrostatic, and capillary forces.

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Formulating a DPI Physical form of the drug substance: high melting point (>80 degC), No significant moisture uptake (probably less than 2% w/w): moisture cause deagglomeration of the compound from the lactose carrier, not taste significantly, and not significantly colored. use of hydrates in DPI formulations can be problematic (potential difficulties with deagglomeration. use of low-solubility salts is to mask the taste of compounds that is unpleasant (lowering the solubility and hence dissolution rate, the taste can often be effectively eliminated) Polymorphic form of the lactose used can affect the aerosolization properties of the formulation: the beta-form was easily entrained but held on to the drug particles most strongly. The anhydrous alfa-form showed the opposite behavior, and the a-form (the monohydrate) showed intermediate behavior. Compatibility of lactose with the drug substance should be assessed, particularly if it is a primary amine Increasing specific surface area and roughness, the effective index of inhalation decreased because of the drug being held more tightly in the inhaled airstream. Characterization of the carrier particles by surface area measurements, SEM, and other solid-state techniques is recommended in preformulation activities for DPIs.

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Some Regulatory guidelines (ICH: International Conference on Harmonization) 1. Q1A (R2) Stability Testing of New Drug Substances and Products (Issued 11/2003, Posted 11/20/2003); 2. Q1B Photostability Testing of New Drug Substances and Products (Issued 11/1996, Reposted 7/7/1998); 3. Q1C Stability Testing for New Dosage Forms (Issued 5/9/1997, Posted 3/19/1998); 4. Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (Issued 1/2003, Posted 1/15/2003); 5. Q3A Impurities in New Drug Substances (Issued 2/10/2003, Posted 2/10/2003); 6. Q3B(R) Impurities in New Drug Products (Issued 11/2003, Posted 11/13/2003); 7. Q3C Impurities: Residual Solvents (Issued 12/24/1997, Posted 12/30/1997); 8. Q6A International Conference on Harmonization; Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (12/29/2000); 9. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (Issued 8/2001, Posted 9/24/2001). Guidelines for herbal (EMEA/botanical as listed in United States) products: 1. Committee for proprietary medicine products (CPMP)/quality working party (QWP)/2819/00 [European Medicines Evaluation Agency (EMEA)/committee on veterinary medicinal products (CVMP)/814/00] Note for Guidance on Quality of Herbal Medicinal Products (CPMP/CVMP adopted July 01). 2. CPMP/QWP/2820/00 (EMEA/CVMP/815/00) Note for Guidance on Specifications: Test procedures and Acceptance Criteria for Herbal Drugs, Herbal Drug Preparations and Herbal Medicinal Products (CPMP/CVMP adopted July 01).

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Thank You all…