Drug excipient interactions and incompatibilities pdf

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drug excipient interactions and incompatibilities pdf

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DOI : Background: Clarithromycin is widely used for infections of helicobacter pylori. Clarithromycin belongs to polymorphic drug. Crystalline state changes of clarithromycin in sustained release tablets were found.

Drug-excipient interaction and its importance in dosage form development

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Excipient interaction has become essential knowledge for rational formulation design of nanoparticles. Nanostructured lipid carriers NLCs include at least three types of excipient, which enhance excipient interaction possibilities and relevance.

The present article introduces an alternative approach for evaluating a great number of excipients with few samples, using NLC as a model delivery system.

This approach is based on two sequential experiments using Hall-2 experimental design and analysis of excipient interactions in respect to their physicochemical properties by multilevel statistics. NLCs were prepared using a hot emulsification-ultrasonication method with lidocaine and nine excipients solid lipids, oils and surfactants.

Following the verified trends, we produced an optimized NLC that exhibited all desirable physicochemical characteristics and a modified drug release profile. Nanostructured lipid carriers NLCs are the second generation of solid lipid nanoparticles SLN , widely used as biodegradable and safe delivery systems for hydrophobic drugs and bioactive substances 1 , 2 , 3.

They are submicron particles of a mixed solid-liquid lipid core coated with surfactants; the carried substance generally being located within the lipid core. In order to obtain reproducible and stable NLCs, they should present low particle size dispersity, high zeta potential in module and constant size range 4. To manipulate these properties, one could alter critical process parameters or formulation parameters. Critical formulation parameters of NLCs include lipid type, amount and melting point; core crystallinity; drug and surfactant properties 5.

Therefore, to perform a rational formulation design, it is crucial to know which excipients interact with each other and change physicochemical attributes. Most of them performed small and isolated experimental full designs with few excipients, which aids formulation improvement but not interaction screening 6 , 7 , 8 , 9 , When screening is prioritized, there is a plethora of design available 11 , but the Plackett-Burman design is probably the most common This design works for robustness assessments that check whether slight factor modifications influence outputs.

Yet, when factors interact with each other, individual outcomes are indistinguishable from interactions Another important type of approach is the application of mixture designs to formulation development, especially for pharmaceutical formulations Nonetheless, in the context of many factors, mixture designs tend to be hard to analyse. Finally, in the case of fractional factorial design, another design type used regularly, main individual factors can be distinguished from others, but two-factor interactions are generally confounded As a non-regular design with two levels, it permits the combination of up to 15 factors in 16 runs, without full aliasing of two main factors We study excipient interaction on physicochemical outcomes of NLCs loaded with lidocaine, but, since two-factor interactions are likely to appear in any significant formulation, this approach applies to any other excipient screenings, from the pharmaceutical to the cosmetics and food fields.

The individual assessments were followed by an NLC fabrication to check physicochemical outputs. In the second stage, we implemented two sequential Hall-2 design experiments with 10 factors. In our method, the excipient levels change throughout the experiments to assess the main effects and two-factor interactions.

This helps to discover tendencies that can serve as criteria for choosing the excipients and for developing optimized formulations. After performing the experiments, we analysed some physicochemical outputs of the resultant NLCs z-average size, dispersity, zeta potential and entrapment efficiency. Then, multilevel analysis was applied to determine variance throughout the two experiments, followed by the formulation of linear models of effects and interactions.

Finally, we fabricated an optimized NLC, according to the output evaluation, to confirm the statistical assessments. First, we need to guarantee complete drug solubilization in all possible formulations. Surfactants augmented LD solubility in water at least two-fold. According to the United States Pharmacopeia USP solubility definition, LD was very soluble in solid lipids, freely soluble in oils and slightly soluble in water and surfactants Partition coefficients were also determined because of their influence on encapsulation rates.

Impurities may decrease LD stability and mask excipient interaction analysis. Therefore, thermal analyses were performed to confirm the purity of super-refined excipients, besides lidocaine encapsulation. LD also presented one narrow melting peak, which indicates purity and meets the range determined by USP for drug identification BW presented a large peak due to its complex mixture of organic compounds, which is in accordance with the reported range 9.

We then fabricated one NLC composed of all excipients, based on excipient quantities from univariate tests data not shown to outline experiments 1 and 2 and perform output analyses. S3 , with spherical shapes and defined borders. Also, the sizes of the nanoparticles were consistent with those determined by DLS data not shown. Consequently, we can analyse the variation across the experiments with a general linear regression model. Since all the formulations reached desirable ZP values smaller than The interactions observed are described in GM applied to exp 2 Supplementary information p.

As displayed in Fig. Polydispersity index PDI distribution from exp 1 and 2 at low and high levels of each excipient a. As their effects were smaller than the others supplementary information p.

We presented Fig. In Fig. This is confirmed in Fig. The choice of these excipients relied on the fact that they strongly contributed to decrease PDI and increase EE, both of which are desirable in most applications. Initially, in the first hour, we can almost see an overlap between the replicates from LD-NLC and the free drug, which may be due to the diffusion of the non-encapsulated LD portion across the membrane barrier. From the second hour on, the releases are quite different, proving that NLC modified the LD release profile.

Pre-formulation studies were essential to confirm high purity levels and compatibility of excipients with lidocaine. In general, ZA size was influenced by the amounts of all excipients, except for liquid lipids in isolation. In accordance with Teeranachaideekul 10 , liquid lipids did not affect particle size in the studied ranges in isolation.

Solid lipids contribute to increase lipid phase viscosity at high wax concentrations 19 , including CP 4 , which affects mixing during NLC production via the hot homogenisation method and leads to particle aggregation and size increase, also increasing size dispersity 4 , 9.

Liquid lipids are not inert, and may have interactions with other excipients, changing nanoparticle size. This CA action may be explained by Hu et al. CA also highlighted its influence amongst the liquid lipids, which decreased PDI at high levels.

Besides that, a diminishment of both ZA and PDI by increasing liquid lipids was observed, which stimulated the formation of nanoparticles with a narrow size distribution due to size reduction 5 , Surfactants acted to decrease ZA, which is in accordance with Helgason et al. According to Helgason et al. The relationship between solid lipids and surfactants depends on the level and type of each factor.

This shows that Gonzalez-Mira et al. They concluded this studying KO because their inputs were proportions of total lipids and surfactants, which do not provide information about interactions among excipients. Our EE results with regard to liquid lipids agreed with Pathak et al.

However, special care relating to a high increase in the liquid lipids amount must be taken, because it may influence the immobilization capacity of the solid lipid and decrease EE The ZA size analysis indicates that, to choose among the levels of each factor, it is necessary to consider the formulation applicability and its desirable size.

In this case, according to the ZA analysis, it would be better to choose CP and CA at low levels and surfactants at high levels. Despite the absence of a general pattern on EE, the analysis permitted us to conclude that we should use PS at higher levels. Finally, optimized NLC presented desirable physicochemical outputs, compatible with the experimental design used for excipient screening. In vitro release kinetics showed a sustained drug release profile, confirming that the final formulation not only solubilized the drug, but also prolonged its release.

We did not intend to cover the influence of each excipient in the LD release kinetics. Noteworthy, Leng et al. As shown by our results, excipient interactions do change physicochemical outputs and are essential to performing a rational NLC formulation. The statistical models were appropriate and elucidated the behaviour of excipient interactions. In addition to the statistical model values, we achieved an optimal formulation of NLC-loaded LD fabricated with highly purified lipids, an ideal feature for future in vivo parenteral studies.

Our method can also be applied to other drug delivery systems as well, with the advantage of a reduced number of samples and, therefore, a cost-effective method for pharmaceutical formulations.

The previous selection of lipids was made according to the following features: natural origin, theoretical capability to solubilize lidocaine, melting point and availability of highly purified samples. The maintenance of the original physical states assures that these physical transitions do not interfere in the physicochemical outcomes among different formulations, masking possible interaction effects.

LD solubility was evaluated as previously reported adapted method described by Joshi and Patravale The determination of LD in the oily phase was obtained through the difference between LD added and LD in the aqueous phase. The partition coefficient was calculated according to Eq. NLCs were prepared using the hot emulsification-ultrasonication method The formulations were cooled in an ice bath until reaching room temperature and were then stored at room temperature.

EE was calculated by the difference between the amount of LD in the formulations and the amount detected in the filtrate, applying Eq. The Zeta potential ZP of these diluted samples was determined by electrophoretic mobility with the same instrument. Blanks were automatically deducted. We performed an experimental plan made up of two sequential experiments.

Since LD was the drug model, its levels remained the same for both experiments. Finally, the experiment outputs were submitted to a multilevel analysis. The statistical analysis of data obtained in 5. The first step was the visualization of the mean values of the factors by mean-level graphs, displayed separately according to experiments 1 and 2 Supplementary Fig. We used an arithmetic mean to obtain the mean values of high and low of each factor level Fig. Representation of the first and second steps of the statistical analysis.

The sequence of steps is organized by letters a to f.

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Abstract: Estriol , is a major urinary estrogen hormone. In this study, thermodynamic and spectroscopic data obtained from pure estriol and mixtures of pure estriol with pharmaceutical excipients were compared. Preliminary studies using thermal and spectroscopic technique implied the compatibility of mannitol, calcium phosphate dibasic, sucrose, butylated hydroxyanisole, cellulose, lactose, magnesium stearate, talc and sodium carboxymethyl cellulose with the drug estriol. As a result of the experimental study, there is incompatibility of estriol-mannitol, estriol-sucrose, estriol-lactose and estriol-magnesium stearate. Zotero Mendeley EndNote. Evaluation of drug-excipient interaction in the formulation of celecoxib tablets. Acta Poloniae Pharmaceutica - Drug Research, 68 3 ,

To facilitate the development of novel drug delivery systems, the demand of new excipients has been increased. Excipients is selected and used because it contributes one or more functional attributes to the product characteristics. The quality of medicines depends not only on the active principles and production processes, but also on the performance of the excipients. In earlier days, excipient s were considered inactive ingredients, but they may have tremendous effect on performance of active pharmaceutical ingredients in dosage form. The magnitude of this effect will depend upon physicochemical properties of drugs as well as quantity and quality of excipients used. Dibrugarh- Assam. Sign In.

Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review Published on Jan 1, in Journal of Excipients and Food Chemicals. Sonali S. Bharate 15 Estimated H-index: View Paper. Add to Collection. The potential physical and chemical interactions between drugs and excipients can affect the chemical nature, the stability and bioavailability of drugs and, consequently, their therapeutic efficacy and safety. The present review covers the literature reports of interaction and incompatibilities of commonly used pharmaceutical excipients with different active pharmaceutical ingredients in solid dosage forms.

Crystal Transition and Drug-excipient Compatibility of Clarithromycin in Sustained Release Tablets

The results show that two multivariate techniques, principal component analysis PCA and cluster analysis CA , can be successfully used for interpretation of TG traces, while the TG is used alone as a screening technique to assess compatibility. The results obtained by using TG analysis, supported by PCA and CA, were approved by those of differential scanning calorimetry, infrared spectroscopy and X-ray powder diffraction. Preformulation stage of solid dosage formulations includes detection of possible interactions of an active pharmaceutical ingredient API with excipients [ 1 — 4 ].

Drug-excipient compatibility studies represent an important phase in drug development. Before a drug substance is formulated into the desired dosage form, there is need for the formulation scientist to fully consider the chemical structure of the drug substance, the type of delivery system required and the proposed manufacturing process. Drug substances are usually combined with excipients which serve different and specialized purpose.

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Preformulation Studies: Drug-Excipient Compatibility Studies

Когда глаза Сьюзан немного привыкли к темноте, она посмотрела на дыру, зияющую в стеклянной стене. Свечение мониторов было очень слабым, но она все же разглядела вдали Хейла, лежащего без движения там, где она его оставила. Стратмора видно не. В ужасе от того, что ее ожидало, она направилась к кабинету шефа. Когда Сьюзан уже сделала несколько шагов, что-то вдруг показалось ей странным. Она остановилась и снова начала вглядываться в глубь помещения Третьего узла. В полумраке ей удалось различить руку Хейла.

Самое странное заключалось в том, что Танкадо, казалось, понимал, что таковы правила игры. Он не дал волю гневу, а лишь преисполнился решимости. Когда службы безопасности выдворяли его из страны, он успел сказать несколько слов Стратмору, причем произнес их с ледяным спокойствием: - Мы все имеем право на тайну. И я постараюсь это право обеспечить. ГЛАВА 7 Мозг Сьюзан лихорадочно работал: Энсей Танкадо написал программу, с помощью которой можно создавать шифры, не поддающиеся взлому. Она никак не могла свыкнуться с этой мыслью. - Цифровая крепость, - сказал Стратмор.

В течение нескольких секунд ни он, ни она не произнесли ни слова.


  • Thank you for visiting nature. Giancarlo Г. - 18.06.2021 at 12:43
  • drug and excipients will potentially affect the product stability and bioavailability. Incompatibility occurring due to complexation of a drug with. Norberta U. - 20.06.2021 at 01:55
  • Abstract: Estriol , is a major urinary estrogen hormone. Alcia C. - 23.06.2021 at 14:29