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Preformulation Of Parenterals Pdf Free

Nanomedicines have paved the way to new opportunities for therapeutic treatments since biocompatible nano-size based particles may enhance the overall pharmacological properties of a given drug substance1, such as improved bioavailability and targeting2, extended release3, decreased side effects4, as well as expanding various administration routes5. Since the last decade, parenteral nanocrystal (NC) suspensions of active pharmaceutical ingredients (APIs) have emerged for various therapies as it was published by our group as a review 1 year ago6. As far as chemotherapy treatments are concerned, many researches lead to the proof of concept for NC preparation and stabilization (e.g. doxorubicin7, hesperetin8,9, hydroxycamptothecin10,11, oridonin12, paclitaxel13,14,15,16,17,18,19, puerarin20, riccardin21, silybin20). However, until the present work, no antitumoral drug has been marketed as a NC preparation for i.v. administration for cancer treatments6,22,23,24. In this study, etoposide (ETO) was prepared for the first time as nanocrystals, using the antisolvent precipitation process. This well-known chemotherapy agent is used against deadliest cancers such as lung, breast, colon or testicular cancer25. ETO inhibits the enzyme topoisomerase II which is crucial in controlling the DNA conformational arrangement by generating double-stranded breaks in the DNA molecule26. Cell death is induced when sufficient covalent topoisomerase-split DNA complexes are formed and stabilized, giving durable DNA strand breaks, switching cells metabolic activity to apoptosis27. In this investigation, agglomerates of ETO NCs were obtained for the first time in a dried powder after slow and complete evaporation of the solvent/antisolvent free of stabilizing agent. Then, the nanocrystals powder was dispersed and stabilized with Pluronic F-127 aqueous solution, allowing a reduction in the non-specific interactions with the immune system, enhancing the in vivo performances. Indeed, as soon as NCs are injected, the proteins present in the bloodstream start binding to the NC surface to form a protein corona. These proteins are acknowledged by the mononuclear phagocyte system (MPS) with rapid clearance of the antigen from the blood. In the present study, stabilization of NCs with F-127 provided a PEG coating advantageous to reduce macrophage interactions and limit the activation of the immune system at least for a single injection28,29,30,31.

Preformulation Of Parenterals Pdf Free


DSC curves for ETO MCs (a), free F-127 ETO NCs (b), F-127 (c), and ETO NCs/F-127 0.03% w/v solid dispersion obtained after evaporation of the continuous medium (d). All DSC thermograms are normalized to the total mass sample. Endothermic signals are pointing down. The inset shows the thermal microscopy micrographs as function of the temperature.

Objectives of salt selection. Innumerable salt forms are available to pharmaceutical scientists. The selection process must therefore be rational and streamlined. A lack of proper planning may lead to the synthesis of several salt forms of the drug candidate for preformulation testing. Moreover, this hit-or-miss approach results in many failures and may cause the loss of test substance and time. These considerations underscore the need for a well-formatted decision tree to help scientists choose a suitable salt form in an efficient and timely manner, depending upon the intended use, with a minimum number of failures and expended resources.

A single salt form generally cannot satisfy all the requirements for developing drug-substance dosage forms. However, introducing a second or third salt form consumes additional developmental resources and increases the cost of manufacturing, handling, storing, and characterizing the additional salt forms. Therefore, the dosage form is developed with a single salt form whenever possible (9). The major drug-development issues are addressed by choosing the appropriate salt form. Minor issues can be addressed using other development tools. Decreasing development timelines intensify the pressure to select the right salt form the first time. Salt selection is a critical step in the preformulation stage of drug development. Gould says that "the balance required in assessing the correct salt from to progress into drug development makes it a difficult semiempirical exercise" (8). This statement emphasizes the need to prioritize the salt-selection process so that various development issues are addressed as early as possible.

Potential candidate for salt formation. The decision about whether salt or free acid or base should be developed depends on these forms' relative pharmaceutical and commercial merits. If the active compound is a liquid, a solid dosage form is usually preferred because oil is difficult to purify, characterize, and maintain in its effective form. Oil is also difficult to transport, sensitive to oxygen, and susceptible to batch-to-batch variations. If the free acid or base is a water-soluble solid with a high melting point, preparing a salt form is generally unnecessary. Alternatively, several useful properties of salt forms may be explored (6).

Pharmacological indications also help determine whether the salt form or the free acid or base should be pursued. For example, when a slow onset or a constant plasma level is required, a highly ionized salt form may be inappropriate if the free acid or base provides a sufficient plasma level. Tolbutamide sodium, an antihyperglycemic agent, causes a rapid fall in blood glucose levels because it is highly ionized. This characteristic causes hypoglycemia in patients with normal insulinomas. Therefore, tolbutamide sodium's corresponding free acid was preferred for oral administration. The salt form's only application is the diagnosis of pancreatic adenomas (30).

Ionic considerations. The degree of ionization is a critical parameter for the physiological performance of the drug and for its formulation development (25). The pKa of the drug and counterion is important for successful salt formation as well. For the preparation of salt forms of basic drugs, the pKa of the counterion should be at least 2 pH lower than the pKa of the drug (34). Similarly, for the preparation of salt forms of acidic drugs, the pKa of the counterion should be at least 2 pH higher than the pKa of the drug. These specifications are required because the counterion must bring the solution's pH to a level lower than the pHmax (see Figure 2) to reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base (5). The generalized rule of difference in pKa units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pKa of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment (35).

Generation of salt forms. Salts can be prepared on a small scale using various methods. Forming salts from free acid or base is the most common method. The free acid or base of the drug substance is combined with the counterion base or acid in specific molar ratios in a suitable solvent system. The salt form is then isolated, and the solid precipitate is recrystallized. A less common method is to form salts through salt exchange. In this method, a counterion salt is treated with a free acid or base in a specific molar concentration in a suitable solvent. The solid is then isolated and recrystallized. The sulfate salt of methyl pyridinium-2-aldoxime was prepared using silver sulfate as a counterion. The unwanted silver ions were removed as insoluble iodide salt, and the desired sulfate salt was precipitated by adding antisolvent (36). A wide range of salts are generally prepared for each new substance. Their properties are compared during a preformulation program that improves the chances of selecting the optimal salt form (29). However, a balanced approach should be adopted because limited resources are available at this early stage of drug development. Commonly used salts such as hydrochlorides and sodium have advantages over other salt-forming moieties. For example, they have low molecular weight and low toxicity. However, other salt forms such as mesylate may sometimes offer advantages such as higher solubility and bioavailability (37).

In spite of the abundance of available counterions, few are used frequently. The preference for pharmaceutical counter-ions is explained by studying the distribution of different counterions of medicinal compounds in USP 2006 (38) (see Table III). The table shows that salt forms of drugs (56.15%) are preferred over free forms (43.85%). Hydrochloride and sodium remain the favorite counterions for the salt formation of medicinal compounds. However, the availability of many pharmaceutically acceptable counterions makes the salt-selection process difficult and cumbersome.

For a rational approach to salt screening, the tiered approach should be combined with a goal-oriented approach in which the main problems associated with the free acid or base are handled first, followed by secondary problems. For example, ranitidine hydrochloride is hygroscopic with a critical relative humidity of approximately 67% (40). However, the hydrochloride salt of ranitidine has better absorption properties compared with the free base and is one of the most successful drugs ever marketed. In a multitiered approach, the hydrochloride salt would have been rejected after hygroscopicity testing, in spite of its better absorption profile (41). High hygroscopicity could be mitigated by developing proper packaging. Similarly, the hydrochloride form of sertaline (i.e., Pfizer's Zoloft) might have been rejected because of its reported 28 polymorphic forms (42). This fact underlines the importance of a goal-oriented approach that addresses the most critical problems first. Less critical problems could be overcome by a proper development strategy. The final salt form selected should have a fine balance of the optimal physicochemical and biopharmaceutical properties. Each stage of salt selection (see Figure 3) is relevant and contributes to the selection of the optimal salt form. However, salt selection can be a difficult task because each salt imparts unique properties to the parent compound.


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