For example, if drug is indicated in the treatment of hypertension, the use of sodium or potassium salt is avoided. In a broader way, it deals with studies of physical, chemical, analytical, and pharmaceutical properties related to molecule and provides idea about suitable modification in molecule to show a better performance. Preformulation is the foremost stage for rational stable, safe and effective product development of an active pharmaceutical ingredient (API). Preformulation studies indicated that the powder blend was not having free flowing nature. In case of hygroscopic material, flow property of drug tends to deteriorate as the presence of absorbed moisture increases cohesiveness. However, in some cases, oxidation can be initiated in presence of light or elevated temperature. Study of these parameters and suitable molecular modification can be linked to generation of effective, safer, stable, and reliable pharmaceutical formulation. As the regulatory perspective, selection of salt form must meet regulatory requirements and must be free from toxicity. Drug substance “powder-in-capsule” (PIC) studies generally avoid the use of excipients – and the compatibility and stability studies associated with their use – for these initial evaluations thereby accelerating early phase product development timelines. Type of crystalline species generated depends on temperature, solvent, and time. Bulk property characterization includes study of polymorphism, crystallinity, density, nature of molecule like deliquescence or hygroscopicity and micromeritic characterization includes study of particle size, shape, porosity, and density. Therapeutic indication is another factor that affects the selection of salt form. Physical form (crystal properties & polymorphism) 6. The generation of the active form must take place with rapid kinetics to ensure effective drug levels at the site of action and to minimize either alternative prodrug metabolism or gradual drug inactivation. Login to your personal dashboard for more detailed statistics on your publications. Various techniques are available to study crystallinity like X-ray, differential scanning microscopy, differential thermal analysis, hot stage microscopy, and the most important one that is scanning electron microscopy. For better clinical performance of the molecule, it has become necessity to study the chirality of the molecule. There are several reasons behind selection of octanol as partitioning solvent, which can be explained as follows: Octanol is believed to mimic the lipoidal character of biological membrane as it contains polar head and nonpolar tail. With respect to stability and solubility, again polymorphs can be classified as stable and metastable polymorphs. If the value of Log P is 0, it indicated that drug has equal distribution in water and partition solvent. Partition coefficient (Log P) value is defined as ratio of unionized drug distributed between aqueous and organic phase. Use of different process to control particle size, shape, and surface area. Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, Second Edition, edited by Mark Gibson For example, the propionic acid derivative naproxen exists in free acid form and has lower water solubility and hence less bioavailability. Moisture level uptake can be monitored by techniques like thermogravimetric analysis (TGA), Karl Fischer titration, and gas chromatography. Thus, it forms an integral part of the drug development process. So study about interaction between active ingredient and inactive ingredient can provide idea about type of incompatibility and the justification behind the inactive ingredient selection [14]. Therefore, preformulation study is an approach for generation of pharmaceutical formulation which utilizes knowledge and area application of toxicology, biochemistry, medicinal chemistry, and analytical chemistry. For example, terbutaline is orally active beta-2-agonist and is indicated in bronchial asthma. Several single enantiomers are preferred over racemic form (e.g., levofloxacin (ofloxacin), esomeprazole (omeprazole), escitalopram (citalopram), and desloratadine (loratadine)) [7]. The ultimate effect of the new chemical entity depends on its availability at the site of action once it is administered through appropriate route in appropriate form. *Address all correspondence to: pinakqa@gmail.com, Pharmaceutical Formulation Design - Recent Practices. In similar way, salt form can improve the taste adaptability by masking the taste and odor. If readily hydrolyzable functional groups are available, then reaction proceeds even at faster rates, making the molecule ineffective. Capecitabine requires triple-phase transformation to be converted to its active form 5-fluorouracil. (, Use techniques to improve surface area or improving solubility by addition of cosolvents or surfactants, Particle shape, size, crystalline/amorphous nature, Smt. Main aim of developing soft drugs is to avoid toxicity associated with formed metabolites. We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers. Each property has significant value in development of formulation. The main reason behind inclusion of this parameter in preformulation is its linkage with other physical parameters like hygroscopicity and particle size and shape. Bulk density: It is defined as total volume occupied by entire powder mass. Brief introduction to this section that descibes Open Access especially from an IntechOpen perspective, Want to get in touch? Correlation between relative humidity, moisture uptake, and flowability. In such an event, they dissolve prematurely and release the drug that is liable to acid degradation or may cause adverse effect in GI, that is, gastric bleeding associated with NSAIDs [17].  Preformulation work is the foundation of developing efficacious and economical formulations. Apart from abovementioned classification, there are two main broad classes of prodrug that are carrier-linked prodrug and bioprecursor prodrug. For example, when the formulation to be developed is suspension, insoluble salt forms like tosylate, estylate, and embonate are the preferred salt forms. Improving unfavorable pharmacokinetic properties: Improving penetration power through membrane. Pharmaceutical Powder Compaction Technology, Second Edition, edited by Metin Celik 198. Many molecular entities exist in racemic form, but only one form gives the desirable pharmacological activity. Drug solubility 2. pKa Determination 3. Crystalline form is characterized by regular spacing between molecular lattices in three-dimensional structure. Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh 199. pKa value determination gives idea about site of absorption. PREFORMULATION: A NEED FOR DOSAGE FORM DESIGN The Concept of Preformulation:-Almost all drugs are marketed as tablets, capsules or both. This improvement can be made in area such as follows: Performance (increased solubility and bioavailability), Improved stability (hydrolytic and thermal stability), Better organoleptic properties (taste masking), Increased patient compliance (decreased side effects). The optimization of molecule is needed with respect to stability of molecule under normal environmental condition or with respect to enhancing the performance of that molecule like bioavailability and stability. In case of creams, crystal growth leads to gritty texture and incase of suppositories one can observe different melting behaviors and leads to formulation instability [12]. In general, one can say that drug-excipient incompatibility may result in change in physical, chemical, microbiological, or therapeutic properties of formulation. 1. It is the extent of ionization that determines the absorption as only unionized form can be absorbed and hence it becomes essential to determine the pKa value of molecule. Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a physicochemically stable and biopharmaceutically suitable dosage form. The main factor that determines the appropriate salt form is type of formulation that is to be developed. It results in formation of insoluble complex with calcium carbonate, leading to slower dissolution and decreased absorption in the gastrointestinal tract [15]. The main objective of determining stability of molecule is to identify the conditions in which molecule is susceptible to deteriorate and to determine degradation pathway. S.M. Shah Pharmacy College, Mehemdabad, India. Submitted: July 16th 2018Reviewed: December 3rd 2018Published: June 9th 2019, Home > Books > Pharmaceutical Formulation Design - Recent Practices. Pre-Formulation Studies By utilizing small quantities of Active Pharmaceutical Ingredients (API) or druggable candidates, our preformulation services can provide valuable information and expertise to guide the compounds towards the next steps. Change in physical appearance of formulation, that is, color, phase conversion. Development of prodrug depends on specific property of drug that needs improvement and mostly with respect to stability, improving bioavailability [2]. Efficient flow of drug substance powder is needed for effective tablet formulation. Hard drugs are opposite to soft drugs, where the modifications are made in such a way that its original properties are retained but are not prone to chemical or biological transformation to avoid generation of metabolites or to increase the biological activity. Preformulation studies are also performed to predict the stability of the formulation during manufacture, transport and storage and thus determine the shelf life of the marketed product. One of the classical examples of such incompatibility is interaction of enteric coated polymers, when administered along with antacids. Amount of moisture absorbed depends on atmospheric conditions and surface area. In carrier-linked prodrug, the drug is linked to a carrier moiety by a temporary covalent linkage. So to avoid the decomposition, the formulation containing vitamin B12 and riboflavin is stored in amber color vials. The prodrug, as well as the in vivo released transport moiety, must be nontoxic. Preformulation studies. Search. This phenomenon is also referred to as solvomorphism. Solubility is not an independent parameter but it relies on several properties like crystal characteristics, temperature, pH, complexation, and molecular structure. For example, use of lithium salt is strictly prohibited. Carrier molecule or functional group can be easily removed in vivo, usually by hydrolytic cleavage [3]. So for this reason, a new challenge is offered after successful pharmaceutical and toxicological screening that is to transform potential active new drug entity into a pharmaceutical formulation. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. HeadquartersIntechOpen Limited5 Princes Gate Court,London, SW7 2QJ,UNITED KINGDOM. Solubility study, partition coefficient determination, UV analysis, HPLC study, FTIR study were also performed. Converting a molecule into a salt form is perhaps the most widely used approach to significantly enhance the performance of a molecule. Utilization of different salts to give environment with different RH. One of the most widely studied techniques during preformulation analysis is solubility profile of drug candidate. The objectives of preformulation studies are to choose the correct form of your drug substance, evaluate its physical properties and generate a thorough understanding of the material's stability under various conditions, leading to the optimal drug delivery system. Most excipients possess biological activity but having role in administration, mediating the release of the active component, and providing stability against degradation. Such interaction results in changes like change in color, odor, flow properties, and sedimentation rate. To generate useful data needed in developing stable and safe dosage forms that can be manufactured on a commercial scale. The highlighted chapter is framed with a vision to provide an in-depth knowledge about pharmaceutical formulation development. Create. The secondary objective preformulation study is to provide longer stability to the formulation by proper designing and protecting drug component from environmental condition and to evaluate performance of developed formulation. Basic drugs having pKa value of around 8 are best absorbed from intestine as they are predominantly present in unionized form. There are several factors that are needed to be considered while selecting appropriate salt form. We are IntechOpen, the world's leading publisher of Open Access books. The resulting changes are more deleterious than physical incompatibility. Particle size greatly affects a number of quality parameters like dissolution rate, solubility, bioavailability, content uniformity, and lack of grittiness. One of the most important advantages associated with amorphous form is the higher solubility and hence the higher dissolution rate. PreformulationPreformulation may be described as a phase of the research and development process where the preformulation scientist characterizes the physical, chemical and mechanical properties of a new drug substance, in order to develop stable, safe and effective dosage form. Successful preformulation requires knowledge of fundamental molecular concepts (solubility, ionisation, partitioning, hygroscopicity and stability) and macroscopic properties (physical form, such as the crystalline … Preformulation study is a phase which is initiated once the new molecule is seeded. Determination of chemical properties indicates the absorption behavior as well as stability of a molecule in the body. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. Change in organoleptic properties of formulation. With sodium and hydrochloride as salt form, there is always enhanced solubility and hence better bioavailability is assured. Bioprecursor prodrug results from a molecular modification of the active principle. Out of all analytical techniques, thermal methods of analysis can provide most positive outcome. Too much reduction in the particle size leads to generation of charged particle and hence unstable system. E$É¿V10120®»–q’ÿ9ž Ãן Normally, flow property of solid drug substance can be measured by Hausner ratio, Carr’s index, and angle of repose, and in case of liquids or semisolid, rheology and thixotropy. The development of an efficient dosage form usually starts with preformulation studies. Most often than not, new chemical entity exists in solid form and the properties under study during preformulation phase are bulk property characterization and micromeritic property characterization. In most of the cases, it can be studied by optical rotatory dispersion and circular dichroism [8]. VxP Pharma Services offers state of the art contract development and manufacturing services, as well as comprehensive preclinical support, for both small molecule and biologics programs.We have extensive experience with a wide range of dosageforms,includingSolid Oral, Liquid Oral,Semi-Solid, Transdermal,Solid Dispersions, Sterile,and lyophilized products to name a few. Irregular particle size and nonuniform shape can also disturb normal flow property of drug. hÞb```¢¬Œ^B ce`aà¸À@&``¸~ö@Õ©v[¦y¹ì[xþ2¾b˜óA»€ƒ•)ùÀr¥.M†W Ù¢)LÛ#"HŠ°.d,ièx •ÃRÌøÙ!Y@¾ƒ}cCz€lËFfɆU Ò{ؗ1ø5.wàÒd28 (à¦ÁÀÀÜè°fƒç_¦Í …$K8=Ÿ4$6àšÀÙæ-Œ»òHµp~fjwHz`ð…k‹Ã„ ² L°^áibšØ°î€²ëu&K†f¥ {™œ4Ôx:™þ3ì½`rmëÚì(òô@bRœr®&aéfwç`ÍKÛöo˜r®®¯eeNF;Ç©’µë{Þ¨Ï_¼P+ZJñÑ\íìÇ֜>Ï_¼ðšv¬£ g¹×­ç[~š%´tã"åÅ`fllž¿EÕ;­Ål^ðڕ=w´óc“ÐÒÍNÒþd»à—ÄÄ 6`çb 0hðœz. Tapped density: It is determined by placing graduated cylinder containing known weight of sample on tapped density apparatus and is operated for the fixed number of taps until a constant volume is attained. Solubility and permeability forms the scientific basis of biopharmaceutics classification system (BCS), which can provide framework for designing type of drug delivery system. 1. In such incompatibility, there is interaction of active pharmaceutical ingredient and excipient through chemical degradation pathway. To inbuilt these virtues into a molecule, efforts are made to optimize a molecule inform of salts, solvates, polymorphs, and more importantly prodrug. In most of the cases, two types of density are studied, namely, bulk density and tapped density. Dissolution rate 5. This could provide important information for formulation design or support the need for molecular modification. Due to lipidic nature of biological membrane, the amount of drug absorbed depends heavily on its lipophilicity. Hausner’s ratio can be represented by the following equation: Table 7 provides the correlation between Carr’s index, Hausner’s ratio, and flowability. Out of these mechanisms, hydrolysis is perhaps the most studied after oxidation. It is absorption of shorter wavelength components that may bring oxidation than longer wavelength components. Preformulation involves the characterization of physical, chemical and microbiological attributes of the drug substance thus providing useful information so as to develop a safe, effective and stable dosage form. Very hygroscopic: After abovementioned storage condition, if overall increase in weight is greater than 15% w/w. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too. It can be broadly elaborated as “a phase which works on study of physical, chemical, analytical, pharmacokinetic, and pharmacodynamic properties of new chemical entity and utilize the obtained results to design and develop an effective, stable, and a safer dosage form.” Preformulation study is there for the multidisciplinary approach and utilizes involvement of several aspects of pharmacology, toxicology, clinical pharmacy, biochemistry, medicinal chemistry, and analytical chemistry (Figure 1). More often than not drugs with low water solubility lead to poor bioavailability and variable clinical response. Discovery of a new drug entity is a huge milestone in science and it becomes even more important if it passes toxicity screening as the potential benefits overweigh the side effects. Effectiveness of molecule therefore depends on hydrolytic stability of molecule. For example, Penicillin G as sodium or potassium salt in crystalline form has the better stability and hence stable and better therapeutic response in comparison to amorphous form. A Preformulation study is an investigation of the physical, chemical, and mechanical properties of a drug substance to develop a safe, effective, and stable dosage form. % ionization can be determined by the following equation: Most of the strong acids and strong bases are present in ionized form throughout GIT and hence poorly absorbed. Amber color bottles do not allow the ultraviolet radiation to pass through, which is the main factor for photodegradation [9]. These investigations are termed preformulation studies. During formulating suspension of an anthelmintic drug oxyclozanide, transformation of unstable polymorph to more stable leads to different crystal size and causes caking. Another factor that determines the type of salt form is type of formulation to be developed. Preformulation study; the term is frequently heard in a pharmaceutical industry. Weakly acidic drugs having pKa value around 4 are best absorbed from stomach as they are predominantly present in unionized form. Log in Sign up. Deliquescent substance absorbs moisture to a greater extent and liquefies itself. Polymorphism is the ability of a compound to crystallize as more than one distinct chemically identical crystalline species with different internal lattices or crystal packing arrangement. However, when it is administered as morpholine salt, the pain at the site of application was reduced to many folds. There are basically two types of methods that are available, which are as follows: Excipients are added along with the active pharmaceutical ingredient in formulations. It was introduced as a sedative agent. In recent times, single enantiomer is dominating the market over the racemate form due to better pharmacological performance. 0 Jurnal Full paper Teknologi Preformulation Studies on LACTUCA SATIVA as Nutraceuticals Granules Nagib Ali Elmarzugia,b*, Eseldin Ibrahim Kelebb, Aref Taleb Mohamedb, Mohamed Salamac, Mariani Abdul Hamida, Wan Rosli Wan Sulaimand, Amal Muftah Hamzae, Hesham Ali El-Enshasya aInstitute of Bioproduct Development, Universiti Teknologi Malaysia, 81310 UTM … As a result, four different solvates are generated. Such type of incompatibility is associated with alteration in drug absorption in the body. 3. Similarly, chloramphenicol palmitate exists in three different polymorphic forms, namely, A, B, and C. Form B has higher solubility and better dissolution profile, while form A is more stable one but low serum concentration was observed. Most of us are known to teratogenic tragedy of thalidomide. Such study is of highest importance when racemic mixture form is used. 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Login to your personal dashboard for more detailed statistics on your publications a sedative agent its bambuterol!, irregular particle size greatly affects a number of quality parameters like rate... Is perhaps the most widely used approach to significantly enhance the performance of physicochemically... To pass through, which involves exposure of molecule therefore depends on specific of! Are carrier-linked prodrug and bioprecursor prodrug results from a molecular modification, oxidation,,... For immediate release formulations, generally sodium or potassium salt of diclofenac, which control! Homogeneity in the favor of amorphous from and hence they are reconstituted before intravenous administration provide knowledge... And time detailed statistics on your publications the extent of oxidation can be classified as stable biopharmaceutically! ) provide additional information permeability with BCS class and associated approach in formulation development tragedy.