Physicochemical Compatibilities: Analyzing Aspects in Four Different Mixtures

Physicochemical Compatibilities: Analyzing Aspects in Four Different Mixtures | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Physicochemical Compatibilities: Analyzing Aspects in Four Different Mixtures Ahmet Özyürek, Zeynep Elif Yeşilyurt-Dirican This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5566976/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: The study investigates the physicochemical compatibility of four drug mixtures commonly used in emergency departments. It aims to address the limited data on intravenous incompatibilities and to enhance clinical practice by identifying potential risks. Methods: Mixtures of pheniramine-dexamethasone, diclofenac-metoclopramide, hyoscine-N-butylbromide-pantoprazole, and metoclopramide-pantoprazole were prepared under simulated emergency department conditions. pH changes were measured at multiple time points (0–60 minutes), and optical density was assessed using a spectrophotometer at specified wavelengths. Visual inspections were conducted immediately after preparation and at regular intervals to detect colour changes, turbidity, precipitation, and gas formation. Compatibility evaluation integrated all these parameters to provide a comprehensive assessment. Results: The diclofenac-metoclopramide mixture exhibited visible turbidity and significant optical density changes (up to 1.89), indicating physical incompatibility. Yellowing was observed in pantoprazole-containing mixtures after 24 hours, raising concerns about stability or incompatibility. Minimal pH changes were recorded across all mixtures, with the largest difference being ±0.3 units. Pheniramine-dexamethasone demonstrated high stability with negligible optical density variations. Conclusion: The diclofenac-metoclopramide mixture is unsuitable for clinical use due to physical incompatibility. Pantoprazole-containing mixtures require further investigation. This study highlights the need for comprehensive compatibility data and recommends cautious use of empirically prepared drug mixtures in emergency settings. Intravenous incompatibility pharmaceutical interactions emergency medicine drug safety Figures Figure 1 Introduction Emergency departments are environments where patients often require the administration of multiple medications. Due to the high patient volume and workload in these settings, certain medications may be administered as mixtures. This practice is often adopted to save both time and resources by combining two or more drugs in the same mixture, within a single syringe, or by utilizing an existing intravenous line via a Y-site. A further critical consideration is that reducing the number of injections or intravenous access points minimizes patient discomfort and pain. However, while some medications are administered as mixtures in emergency departments or other clinical units, data on the compatibility of these mixtures, as well as practitioners' knowledge in this area, may be insufficient for many drugs [ 1 ]. Therefore, data on IV incompatibility should be increased [ 2 ]. Awareness of existing knowledge regarding IV incompatibility and how to access such information may be insufficient among healthcare professionals. A significant issue frequently encountered in practice is the confusion between IV incompatibility and pharmacodynamic or pharmacokinetic interactions, as well as the reliance on platforms like Drugs.com or UpToDate.com for verification. Notably, the drug interactions module on Drugs.com Interaction Checker is unrelated to IV incompatibility, which pertains specifically to pharmaceutical interactions. In emergency departments, mixtures that are still used empirically or conservatively, without knowing whether they can be safely combined, remain common in practice. Greater emphasis should be placed on identifying which of these mixtures are supported by scientific evidence and which are not. Examples include diclofenac-thiocolchicoside (in the same syringe), pheniramine hydrogen maleate-dexamethasone 21-phosphate disodium (in normal saline), diclofenac sodium-metoclopramide HCl monohydrate (in the same syringe), and hyoscine-N-butylbromide-ranitidine hydrochloride-metoclopramide HCl monohydrate (in normal saline). The parenteral administration of thiocolchicoside and pheniramine hydrogen maleate is common in some countries but not in others, which may explain why these drugs or their interaction results are absent from pharmaceutical interaction modules in applications such as Micromedex and UpToDate Lexidrug (which both utilize Trissel). In countries where these databases are widely used, this absence may be perceived as a limitation. Although interactions can be researched on platforms like PubMed or Google Scholar, physicians using these databases might interpret the absence of a drug name as indicating "no interaction" or may lack the time or willingness to conduct a thorough literature review. Another issue observed in emergency practice related to IV incompatibility is that some emergency physicians do not consider colour changes when two drugs are mixed as a problem (e.g., the mixture of dexketoprofen and thiocolchicoside). As clinical experience grows, the importance of raising awareness on this topic becomes increasingly evident. To address these challenges, a table listing the most frequently used drugs could be prepared for each country or hospital. This would facilitate the work of both physicians and healthcare personnel administering medications while increasing confidence in practice. Before preparing such tables, necessary studies should be conducted on drugs with little or no compatibility data. For instance, in our country, the previously common mixture of hyoscine-N-butylbromide, Ulcuran (ranitidine), and metoclopramide is no longer used due to the withdrawal of Ulcuran. Physicians now seek alternatives to Ulcuran and question the IV incompatibility of frequently used emergency drugs, such as pantoprazole. While we could not find compatibility data for combination of pantoprazole and metoclopramide in many sources, incompatibility information for this was available only in the Stabilis.org database [ 1 , 3 ]. This mixture serves as another example of the differences between databases. We could not find any incompatibility data between pheniramine and dexamethasone, diclofenac and metoclopramide, or hyoscine-N-butylbromide and pantoprazole. The fact that pantoprazole has been identified in some studies as the drug most frequently causing physicochemical incompatibility [ 1 , 4 ], highlights the importance of focusing on its IV incompatibility. Materials From local pharmacies, the following were obtained: 100 mL of normal saline (Polifleks 0.9% Isotonic Sodium Chloride IV Infusion Solution, Polifarma, Türkiye), 150 mL of hypertonic sodium chloride solution (Polifleks 3% Hypertonic Sodium Chloride IV Infusion Solution, Polifarma İlaç San. ve Tic. A.Ş., Türkiye), dexamethasone 21-phosphate disodium injection solution (Dekort 8 mg/2 mL, Deva, Türkiye), pheniramine hydrogen maleate injection solution (Avil 45.5 mg/2 mL, Sandoz, Türkiye), diclofenac sodium solution (Dikloron 75 mg/3 mL, Deva, Türkiye), metoclopramide HCl monohydrate solution (Metpamid 10 mg/2 mL, Sifar, Türkiye), hyoscine-N-butylbromide solution (Buscopan 20 mg/mL, Sanofi [Opella Healthcare], Türkiye), and pantoprazole sodium sesquihydrate lyophilized powder for solution preparation (Pulcet 40 mg, Nobel, Türkiye and Progas 40 mg, VEM, Türkiye). Syringes with hypodermic needles featuring polyisoprene rubber gaskets, polypropylene barrels, and PP/PE plungers (b-good, Risus, Türkiye) were also purchased. Methods To adapt to the usage and conditions in the emergency department, the mixtures were prepared in a manner similar to routine practice conditions and applications. Pheniramine and dexamethasone were sequentially added to 100 mL of normal saline using separate syringes. Diclofenac and metoclopramide were drawn into the same syringe. Pantoprazole and hyoscine were mixed in 100 mL of normal saline using separate syringes. Metoclopramide and pantoprazole were added to a 3% hypertonic NaCl solution using separate syringes. The mixtures were transferred into centrifuge tubes (ISOLAB, Germany) for use in the analysis process. Initial pH measurements were taken immediately after the preparation of the mixtures (OHAUS Starter 2100 pH Meter). Considering the timeframes during which medications are administered to patients in the emergency department, pH measurements were conducted at 0, 5, 10, 15, and 20 minutes, as well as at 60 minutes to observe medium-to-long-term effects. pH changes not exceeding 0.5 units were considered insignificant. To evaluate optical changes that are not visible to the naked eye, the mixtures were placed in an absorbance plate reader (SpectraMax ABS Plus) after completing the pH measurements. Separate measurements were performed using serum and distilled water as blanks. The measurements were conducted at wavelengths of 350, 410, 547, and 550 nm, based on previous studies and guidelines [ 5 , 6 ]. Samples from each mixture were placed into two wells. The mixtures were stored, and new mixtures were prepared. In these new mixtures, full spectrum measurements (200–800 nm, step: 50) were conducted at 0, 5, 10, 15, 20, 30, 40, 50, and 60 minutes. Three wells were filled for each sample [ 5 , 7 ]. Throughout the study, experiments were conducted at room temperature (average 25–28°C). To simulate emergency department conditions, the mixtures were prepared in a laboratory illuminated by standard fluorescent lighting, without protection from light or temperature control [ 5 , 6 , 8 ]. The measurements were conducted in the laboratories of Gazi University. Since this was an in vitro study, ethics committee approval was not required. Results When diclofenac and metoclopramide were mixed, the colour turned white. Over the course of the study, the colour gradually lightened, and by the 1st hour, the mixture was nearly transparent (Fig. 1 ). Such a phenomenon was not observed in other mixtures. Upon macroscopic examination of the mixtures the following day, yellowing was noted in solutions containing pantoprazole. No precipitation or gas formation was observed in any mixture. Turbidity was only detected in the diclofenac-metoclopramide mixture. The optical density values when the blanks are respectively saline and distilled water are given in Table 1 and Table 2 . Table 1 Optical density values of the mixtures when normal saline is used as the blank Pheniramine Dexamethasone Diclofenac Metoclopramide Hyoscine-N-butylbromide Pulcet Metoclopramide Progas 350 nm -0,002 0.001 0.076 0,083 0.018 0.020 0.033 0.017 410 nm -0.002 -0.002 0.036 0.040 0.001 0.002 0.006 0.002 547 nm -0.002 -0.000 0.022 0.024 0.000 0.001 0.007 0.000 550 nm -0.002 0.001 0.018 0.020 -0.001 0.000 -0.000 0.001 Table 2 Optical density values of the mixtures when distilled water is used as the blank Pheniramine Dexamethasone Diclofenac Metoclopramide Hyoscine-N-butylbromide Pulcet Metoclopramide Progas 350 nm -0,001 0.002 0.087 0,098 0.017 0.020 0.022 0.017 410 nm -0.001 -0.000 0.027 0.031 0.002 0.003 0.003 0.003 547 nm -0.001 -0.001 0.020 0.022 0.000 0.001 0.001 0.001 550 nm -0.001 -0.001 0.018 0.020 0.000 0.001 0.001 0.001 The pH values of the mixtures at different times are shown in Table 3 , and the calculated differences between these values are presented in Table 4 . Table 3 pH values of the mixtures at different time points 0 min 5 min 10 min 15 min 20 min 60 min Pheniramine Dexamethasone 5,64 5,69 5,57 5,62 5,66 5,76 Diclofenac Metoclopramide 6,96 7,03 7,00 6,99 7,12 7,17 Hyoscine Pulcet 8,76 8,65 8,75 8,76 8,70 8,46 Metoclopramide Progas 8,01 7,95 7,93 7,93 7,99 7,97 Table 4 pH changes between different time points of the mixtures 0–5 5–10 10–15 15–20 20–60 0–10 0–15 0–20 0–60 5–15 5–20 5–60 10–20 10–60 15–60 1 + 0,05 -0,12 + 0,05 + 0,04 + 0,1 -0,07 -0,02 + 0,02 + 0,12 -0,07 -0,03 + 0,07 + 0,09 + 0,19 + 0,14 2 + 0,07 -0,03 -0,01 + 0,13 + 0,05 + 0,04 + 0,03 + 0,16 + 0,21 -0,04 + 0,09 + 0,14 + 0,12 + 0,17 + 0,18 3 -0,11 + 0,1 + 0,01 − 0,06 -0,24 -0,01 0 -0,06 − 0,3 + 0,11 + 0,05 − 0,19 − 0,05 − 0,29 − 0,3 4 -0,06 -0,02 0 + 0,06 -0,02 -0,08 -0,08 -0,02 -0,04 -0,02 + 0,04 + 0,02 + 0,06 + 0,04 + 0,04 1. Pheniramine−Dexamethasone, 2. Diclofenac−Metoclopramide, 3. Hyoscine−N−butylbromide−Pulcet, 4. Metoclopramide−Progas The greatest pH differences were observed as follows: for pheniramine-dexamethasone between the 10th and 60th minutes (+ 0.19), for diclofenac-metoclopramide between the 0th and 60th minutes (+ 0.21), for hyoscine-N-butylbromide-Pulcet between the 0th and 60th minutes and the 15th and 60th minutes (-0.3), and for metoclopramide-Progas between the 0th and 10th minutes and the 0th and 15th minutes (-0.08). At wavelengths of 350, 400, and 550 nm, the maximum change within one hour was 0.01 for pheniramine-dexamethasone, 1.89 for diclofenac-metoclopramide, 0.14 for buscopan-pantoprazole, and 0.03 for metoclopramide-pantoprazole (Table 5 ). Table 5 Optical density values of the mixtures at different wavelengths 350 nm 400 nm 550 nm Mixture Well Min Max diff Min Max diff Min Max diff Pheniramine Dexamethasone 1 0,05 0,05 0 0,04 0,04 0 0,04 0,04 0 2 0,06 0,06 0 0,04 0,05 0,01 0,04 0,05 0,01 3 0,05 0,06 0,01 0,04 0,05 0,01 0,04 0,04 0 Diclofenac Metoclopramide 1 0,57 2,46 1,89 0,43 2,23 1,8 0,37 2,15 1,78 2 0,64 2,45 1,81 0,47 2,22 1,75 0,45 2,14 1,69 3 0,6 2,44 1,84 0,45 2,21 1,76 0,42 2,13 1,71 Hyoscine Pulcet 1 0,19 0,33 0,14 0,15 0,29 0,14 0,12 0,25 0,13 2 0,07 0,08 0,01 0,05 0,05 0 0,04 0,05 0,01 3 0,07 0,08 0,01 0,04 0,05 0,01 0,03 0,05 0,02 Metoclopramide Progas 1 0,06 0,07 0,01 0,04 0,04 0 0,04 0,04 0 2 0,07 0,08 0,01 0,05 0,06 0,01 0,04 0,05 0,01 3 0,1 0,13 0,03 0,08 0,1 0,02 0,07 0,09 0,02 Discussion When examined with the naked eye, a colour change was observed only in the diclofenac-metoclopramide mixture. At the moment the two drugs were mixed, the colour turned white. Since this indicates a failure to meet one of the conditions for physical compatibility, emergency physicians should avoid preparing this mixture in routine practice. Additionally, as no more than 3 mL of medication should be administered in a single IM injection to a well-developed adult [ 9 ] the resulting mixture (5 mL) exceeds the recommended volume. To prevent tissue damage, attention should be paid not only to physical incompatibility but also to this volume issue. Another example that should be noted in this context is the diclofenac-thiocolchicoside mixture (3 + 2 = 5 mL), which is commonly used in our emergency departments. In the IV compatibility section of Clinical Pharmacology powered by ClinicalKey [ 10 ], it is stated that diclofenac and thiocolchicoside are compatible when mixed in the same syringe. However, in UpToDate Lexidrug [ 11 ], no selectable option appears when searching for thiocolchicoside to evaluate incompatibility. Similarly, the Micromedex IV compatibility [ 12 ] assessment does not provide any results for this combination. Furthermore, the outdated reference provided by Clinical Pharmacology for this mixture suggests the need for further evaluation. Yellowing was observed in the solutions containing pantoprazole after one day; however, it could not be determined whether this was due to IV incompatibility or the duration for which pantoprazole remains stable in solution (incompatibility versus instability). The product label includes the following information: “The product must be used immediately from a microbiological perspective. If not used immediately, the storage duration and conditions during use are the responsibility of the user, and this period should not normally exceed 12 hours at 25°C.” Another noteworthy point in our study is that, due to updates made at different times to the usage instructions of different pantoprazole preparations, one of the preparations we used states: “Stable for 12 hours at 25°C after reconstitution and dilution with the following solutions: Reconstitution with 10 mL of 0.9% NaCl solution; reconstitution with 10 mL of 0.9% NaCl solution followed by dilution with 100 mL of 0.9% NaCl solution; reconstitution with 10 mL of 0.9% NaCl solution followed by dilution with 100 mL of 5% dextrose solution.” However, with a recent update this year, this section has been revised to: “Stable for 12 hours at 25°C after reconstitution and dilution.” [ 13 ]. The new update is more practical and less confusing because it eliminates the possibility that users might assume issues only arise with specific mixtures listed and that there is no data available for other combinations. When examining the changes in OD values within 1 hour, the values for pheniramine-dexamethasone showed almost no variation across all three mixtures. Therefore, this mixture was considered compatible. In contrast, the OD values for diclofenac-metoclopramide exhibited changes of up to 1.89, which was an expected outcome due to the visible changes observed with the naked eye. For buscopan-pantoprazole, the maximum change was found to be 0.14; however, this change was observed in only one well, while the maximum changes in the other two wells were 0.01 and 0.02. Thus, no definitive conclusion could be drawn. The same situation was observed for the metoclopramide-pantoprazole mixture. Considering previous guidelines and studies, the changes in pH values within the examined time intervals were too small to be considered significant. Given that pH changes during the first 20 minutes were minimal and that medications are typically administered within a relatively short time in emergency department practice, no incompatibility could be identified based on pH evaluation. However, potential scenarios, such as the need to prepare medications in advance due to the workload in emergency departments or delays in administration for other reasons, should not be overlooked. As with other studies utilizing biochemical methods, it would be beneficial to re-evaluate the drugs examined in this study. Another factor necessitating the repetition of incompatibility studies is the potential role of excipients in interactions. Brousseau et al. reported that when they began sourcing dexamethasone from a new supplier, precipitation occurred in mixtures prepared with the new formulation, unlike with the previous one [ 14 ]. In the formulation obtained from the previous supplier, methylparaben/propylparaben were used as preservatives, whereas benzyl alcohol was used in the preparation from the new supplier. To assist future studies, incompatibility studies should also specify the excipients present in the formulations. In our study, the excipients for the drugs used were as follows: for metoclopramide, sodium chloride, sodium metabisulfite, and distilled water; for pheniramine, water for injection; for dexamethasone, creatinine, phenol, sodium citrate dihydrate, sodium hydroxide, sodium metabisulfite, and water for injection; for diclofenac, mannitol, sodium metabisulfite, benzyl alcohol, propylene glycol, sodium hydroxide, and water for injection; for pantoprazole (Progas), sodium hydroxide and water for injection; and for pantoprazole (Pulcet), disodium EDTA and sodium hydroxide. When evaluating incompatibility in clinical practice or examining interaction results, these details should also be compared as much as possible. In addition to the active ingredient, information on preservatives and carriers (e.g., pockets or syringes) as well as materials (e.g., polypropylene) can also be found in resources such as Thériaque, where these factors can be selected and analyzed. [ 15 ]. To improve or expand these resources, the materials used, as well as excipients, should be specified and compared when necessary in clinical practice. In our study, pheniramine and dexamethasone were sequentially added to saline using separate syringes. This approach was taken because the dosage of drugs is a critical factor in IV incompatibility, and one of the reasons syringe compatibility and solution compatibility are distinct scenarios. However, if the practitioner uses the same syringe to draw drugs directly from ampoules/vials, this could lead to different outcomes. Therefore, if data on syringe compatibility are available, it may be beneficial to consider them as well. This study focused on the physical compatibility of the drugs. While pH evaluation is part of chemical compatibility assessment, it alone is insufficient to determine whether two mixtures are compatible. Chemical evaluation requires more advanced and extensive analyses (e.g., HPLC, LC/GC-MS). Nevertheless, any mixtures showing evidence of physical or chemical incompatibility should be avoided in clinical use. Additional studies are required to make mixtures that appear compatible more applicable in clinical practice. Pharmacopoeia methods and the minimum requirements outlined in the guideline prepared following the European Consensus Conference [ 5 ] should be taken into consideration in studies; however, it is beneficial to utilize as many methods as possible. Healthcare professionals need to learn which resources they can use for information on IV incompatibility. When choosing among these resources, they should identify the differences between them and determine which one is most suitable for their practice. They should also be able to consult with a clinical pharmacologist or pharmacist about potential mixtures for which they cannot find data or wish to learn more. Declarations Funding No funds, grants, or other support was received. Competing Interests The authors have no competing interests to declare that are relevant to the content of this article. Ethics Approval Not applicable. Data availability Available upon request. Contributions of Authors statement AO designed the study. AO: performing experiments, data analyses, writing the original draft. ZEYD: support on performing experiments and review of the manuscript. References Maison O, Tardy C, Cabelguenne D, et al (2019) Drug incompatibilities in intravenous therapy: evaluation and proposition of preventive tools in intensive care and hematology units. Eur J Clin Pharmacol 75:179–187. https://doi.org/10.1007/s00228-018-2602-6 Marsilio NR, Silva D da, Bueno D (2016) Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva 28:147–153. https://doi.org/10.5935/0103-507X.20160029 Stabilis 4.0. https://www.stabilis.org/. Accessed 2 Sep 2024 Sriram S, Aishwarya S, Moithu A, et al (2020) Intravenous Drug Incompatibilities in the Intensive Care Unit of a Tertiary Care Hospital in India: Are they Preventable? J Res Pharm Pract 9:106. https://doi.org/10.4103/jrpp.JRPP_20_11 Bardin C, Astier A, Vulto A, et al (2011) Guidelines for the practical stability studies of anticancer drugs: A European consensus conference. Ann Pharm Fr 69:221–231. https://doi.org/10.1016/j.pharma.2011.07.002 Cruz KCE, Churchwell MD, Mauro VF, Boddu SHS (2018) Physical compatibility of levetiracetam injection with heparin, dobutamine, and dopamine. Am J Health-Syst Pharm AJHP Off J Am Soc Health-Syst Pharm 75:510–512. https://doi.org/10.2146/ajhp180069 Youssef SH, Garg A, Song Y, et al (2024) Harmonising IV Oxycodone with Paediatric Perioperative Medications: A Compatibility Study Through Y-Type Connectors. Drug Des Devel Ther 18:899–908. https://doi.org/10.2147/DDDT.S444581 Yliruusi JK, Sothmann AG, Laine RH, et al (1982) Sorptive loss of diazepam and nitroglycerin from solutions to three types of containers. Am J Hosp Pharm 39:1018–1021 Elsevier (2024) Medication Administration: Intramuscular Injections - Acute care. In: Medicat. Adm. Intramuscular Inject. - Acute Care. https://elsevier.health/en-US/preview/intramuscular-injections-acute-care. Accessed 21 Aug 2024 Clinical Pharmacology powered by ClinicalKey | Elsevier. In: www.elsevier.com. https://www.elsevier.com/products/clinicalkey/clinical-pharmacology. Accessed 10 Oct 2024 UpToDate Lexidrug. https://online.lexi.com/. Accessed 10 Oct 2024 Micromedex. https://www.micromedexsolutions.com/home/dispatch/. Accessed 10 Oct 2024 Küb/Kt Listesi. https://www.titck.gov.tr/kubkt. Accessed 10 Oct 2024 Brousseau P, Nickerson J, Dobson G (2007) Dexamethasone and ondansetron incompatibility in polypropylene syringes. Can J Anesth 54:953–954. https://doi.org/10.1007/BF03026805 Thériaque. https://www.theriaque.org/apps/contenu/journal.php?menu=4. Accessed 2 Sep 2024 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5566976","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":390947152,"identity":"d6edf853-fbf2-465c-ada3-4d6beb0eabec","order_by":0,"name":"Ahmet Özyürek","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYDCCAwxsyDwbIMHcABImpMUAxktjYGBjJE3LYcJa+G4ffvboRsUfOfkZOWYfPpw5L2dwv7HxwYczDPL8Ytj1SZ5LMzfOOWNgzDgjx3jmjBu3jQ2OMTYbzrjBYDhzdgJWLQZnGMykc9sMEpslcoyZeT7cTtxwjLFNmucDQ4LBbVxa2L9J5/4zSGwDafnz4RwxWniAtjQYJPaAtDDcOADVcgO3FskzPGXSOceMjSV4nhUz9pxJNpY8lgj0yxkJnH7hO8O+TTqnRk5Ovj15M8OPY3ZyfIcPH3zw4ZiNPL80di0IIICqQIKAchDgP0CEolEwCkbBKBiRAADUyGQFLDYgPwAAAABJRU5ErkJggg==","orcid":"","institution":"Turkish Medicines and Medical Devices Agency","correspondingAuthor":true,"prefix":"","firstName":"Ahmet","middleName":"","lastName":"Özyürek","suffix":""},{"id":390947153,"identity":"23f77b4a-a2c5-45e8-9993-4eb0974d326b","order_by":1,"name":"Zeynep Elif Yeşilyurt-Dirican","email":"","orcid":"","institution":"Gazi University","correspondingAuthor":false,"prefix":"","firstName":"Zeynep","middleName":"Elif","lastName":"Yeşilyurt-Dirican","suffix":""}],"badges":[],"createdAt":"2024-12-02 21:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5566976/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5566976/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71603109,"identity":"00320897-5928-4b67-9257-257ccb9fe41f","added_by":"auto","created_at":"2024-12-17 05:57:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":335224,"visible":true,"origin":"","legend":"\u003cp\u003eAppearance of the diclofenac-metoclopramide mixture after 1 hour and at the beginning\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5566976/v1/3532300beb72bf4ca75cb8ed.png"},{"id":71604566,"identity":"5e634e42-fb5b-497d-99c6-2a1a0ac1aa28","added_by":"auto","created_at":"2024-12-17 06:05:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020446,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5566976/v1/45924248-877d-492d-bbf9-b4811fa09535.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Physicochemical Compatibilities: Analyzing Aspects in Four Different Mixtures","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEmergency departments are environments where patients often require the administration of multiple medications. Due to the high patient volume and workload in these settings, certain medications may be administered as mixtures. This practice is often adopted to save both time and resources by combining two or more drugs in the same mixture, within a single syringe, or by utilizing an existing intravenous line via a Y-site. A further critical consideration is that reducing the number of injections or intravenous access points minimizes patient discomfort and pain. However, while some medications are administered as mixtures in emergency departments or other clinical units, data on the compatibility of these mixtures, as well as practitioners' knowledge in this area, may be insufficient for many drugs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Therefore, data on IV incompatibility should be increased [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Awareness of existing knowledge regarding IV incompatibility and how to access such information may be insufficient among healthcare professionals. A significant issue frequently encountered in practice is the confusion between IV incompatibility and pharmacodynamic or pharmacokinetic interactions, as well as the reliance on platforms like Drugs.com or UpToDate.com for verification. Notably, the drug interactions module on Drugs.com Interaction Checker is unrelated to IV incompatibility, which pertains specifically to pharmaceutical interactions. In emergency departments, mixtures that are still used empirically or conservatively, without knowing whether they can be safely combined, remain common in practice. Greater emphasis should be placed on identifying which of these mixtures are supported by scientific evidence and which are not. Examples include diclofenac-thiocolchicoside (in the same syringe), pheniramine hydrogen maleate-dexamethasone 21-phosphate disodium (in normal saline), diclofenac sodium-metoclopramide HCl monohydrate (in the same syringe), and hyoscine-N-butylbromide-ranitidine hydrochloride-metoclopramide HCl monohydrate (in normal saline). The parenteral administration of thiocolchicoside and pheniramine hydrogen maleate is common in some countries but not in others, which may explain why these drugs or their interaction results are absent from pharmaceutical interaction modules in applications such as Micromedex and UpToDate Lexidrug (which both utilize Trissel). In countries where these databases are widely used, this absence may be perceived as a limitation.\u003c/p\u003e \u003cp\u003eAlthough interactions can be researched on platforms like PubMed or Google Scholar, physicians using these databases might interpret the absence of a drug name as indicating \"no interaction\" or may lack the time or willingness to conduct a thorough literature review. Another issue observed in emergency practice related to IV incompatibility is that some emergency physicians do not consider colour changes when two drugs are mixed as a problem (e.g., the mixture of dexketoprofen and thiocolchicoside). As clinical experience grows, the importance of raising awareness on this topic becomes increasingly evident. To address these challenges, a table listing the most frequently used drugs could be prepared for each country or hospital. This would facilitate the work of both physicians and healthcare personnel administering medications while increasing confidence in practice. Before preparing such tables, necessary studies should be conducted on drugs with little or no compatibility data. For instance, in our country, the previously common mixture of hyoscine-N-butylbromide, Ulcuran (ranitidine), and metoclopramide is no longer used due to the withdrawal of Ulcuran. Physicians now seek alternatives to Ulcuran and question the IV incompatibility of frequently used emergency drugs, such as pantoprazole. While we could not find compatibility data for combination of pantoprazole and metoclopramide in many sources, incompatibility information for this was available only in the Stabilis.org database [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This mixture serves as another example of the differences between databases. We could not find any incompatibility data between pheniramine and dexamethasone, diclofenac and metoclopramide, or hyoscine-N-butylbromide and pantoprazole. The fact that pantoprazole has been identified in some studies as the drug most frequently causing physicochemical incompatibility [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], highlights the importance of focusing on its IV incompatibility.\u003c/p\u003e"},{"header":"Materials","content":"\u003cp\u003eFrom local pharmacies, the following were obtained: 100 mL of normal saline (Polifleks 0.9% Isotonic Sodium Chloride IV Infusion Solution, Polifarma, T\u0026uuml;rkiye), 150 mL of hypertonic sodium chloride solution (Polifleks 3% Hypertonic Sodium Chloride IV Infusion Solution, Polifarma İla\u0026ccedil; San. ve Tic. A.Ş., T\u0026uuml;rkiye), dexamethasone 21-phosphate disodium injection solution (Dekort 8 mg/2 mL, Deva, T\u0026uuml;rkiye), pheniramine hydrogen maleate injection solution (Avil 45.5 mg/2 mL, Sandoz, T\u0026uuml;rkiye), diclofenac sodium solution (Dikloron 75 mg/3 mL, Deva, T\u0026uuml;rkiye), metoclopramide HCl monohydrate solution (Metpamid 10 mg/2 mL, Sifar, T\u0026uuml;rkiye), hyoscine-N-butylbromide solution (Buscopan 20 mg/mL, Sanofi [Opella Healthcare], T\u0026uuml;rkiye), and pantoprazole sodium sesquihydrate lyophilized powder for solution preparation (Pulcet 40 mg, Nobel, T\u0026uuml;rkiye and Progas 40 mg, VEM, T\u0026uuml;rkiye). Syringes with hypodermic needles featuring polyisoprene rubber gaskets, polypropylene barrels, and PP/PE plungers (b-good, Risus, T\u0026uuml;rkiye) were also purchased.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTo adapt to the usage and conditions in the emergency department, the mixtures were prepared in a manner similar to routine practice conditions and applications. Pheniramine and dexamethasone were sequentially added to 100 mL of normal saline using separate syringes. Diclofenac and metoclopramide were drawn into the same syringe. Pantoprazole and hyoscine were mixed in 100 mL of normal saline using separate syringes. Metoclopramide and pantoprazole were added to a 3% hypertonic NaCl solution using separate syringes.\u003c/p\u003e \u003cp\u003eThe mixtures were transferred into centrifuge tubes (ISOLAB, Germany) for use in the analysis process. Initial pH measurements were taken immediately after the preparation of the mixtures (OHAUS Starter 2100 pH Meter). Considering the timeframes during which medications are administered to patients in the emergency department, pH measurements were conducted at 0, 5, 10, 15, and 20 minutes, as well as at 60 minutes to observe medium-to-long-term effects. pH changes not exceeding 0.5 units were considered insignificant.\u003c/p\u003e \u003cp\u003eTo evaluate optical changes that are not visible to the naked eye, the mixtures were placed in an absorbance plate reader (SpectraMax ABS Plus) after completing the pH measurements. Separate measurements were performed using serum and distilled water as blanks. The measurements were conducted at wavelengths of 350, 410, 547, and 550 nm, based on previous studies and guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Samples from each mixture were placed into two wells. The mixtures were stored, and new mixtures were prepared. In these new mixtures, full spectrum measurements (200\u0026ndash;800 nm, step: 50) were conducted at 0, 5, 10, 15, 20, 30, 40, 50, and 60 minutes. Three wells were filled for each sample [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThroughout the study, experiments were conducted at room temperature (average 25\u0026ndash;28\u0026deg;C). To simulate emergency department conditions, the mixtures were prepared in a laboratory illuminated by standard fluorescent lighting, without protection from light or temperature control [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe measurements were conducted in the laboratories of Gazi University. Since this was an \u003cem\u003ein vitro\u003c/em\u003e study, ethics committee approval was not required.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWhen diclofenac and metoclopramide were mixed, the colour turned white. Over the course of the study, the colour gradually lightened, and by the 1st hour, the mixture was nearly transparent (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Such a phenomenon was not observed in other mixtures. Upon macroscopic examination of the mixtures the following day, yellowing was noted in solutions containing pantoprazole. No precipitation or gas formation was observed in any mixture. Turbidity was only detected in the diclofenac-metoclopramide mixture.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe optical density values when the blanks are respectively saline and distilled water are given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOptical density values of the mixtures when normal saline is used as the blank\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePheniramine Dexamethasone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eDiclofenac Metoclopramide\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eHyoscine-N-butylbromide Pulcet\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eMetoclopramide Progas\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e350 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0,002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e410 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e547 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e550 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOptical density values of the mixtures when distilled water is used as the blank\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePheniramine Dexamethasone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eDiclofenac Metoclopramide\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eHyoscine-N-butylbromide Pulcet\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eMetoclopramide Progas\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e350 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0,001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,098\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e410 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e547 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e550 nm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe pH values of the mixtures at different times are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and the calculated differences between these values are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003epH values of the mixtures at different time points\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20 min\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60 min\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePheniramine Dexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5,64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5,69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5,62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5,66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5,76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiclofenac Metoclopramide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6,96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7,00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6,99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7,12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7,17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyoscine\u003c/p\u003e \u003cp\u003ePulcet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8,76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8,65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8,75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8,76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8,70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8,46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetoclopramide Progas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7,95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7,93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7,93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7,99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7,97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003epH changes between different time points of the mixtures\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u0026ndash;10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u0026ndash;15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u0026ndash;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u0026ndash;60\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u0026ndash;10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u0026ndash;15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u0026ndash;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u0026ndash;60\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u0026ndash;15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003e5\u0026ndash;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5\u0026ndash;60\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003e10\u0026ndash;20\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003e10\u0026ndash;60\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c16\"\u003e \u003cp\u003e15\u0026ndash;60\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0,12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u0026thinsp;0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;0,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u0026thinsp;0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;0,12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u0026thinsp;0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u0026thinsp;0,09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u0026thinsp;0,19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e+\u0026thinsp;0,14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e+\u0026thinsp;0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u0026thinsp;0,13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u0026thinsp;0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;0,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u0026thinsp;0,16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u0026thinsp;0,21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e+\u0026thinsp;0,09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u0026thinsp;0,14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u0026thinsp;0,12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u0026thinsp;0,17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e+\u0026thinsp;0,18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0,11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e+\u0026thinsp;0,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0,24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e+\u0026thinsp;0,11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e+\u0026thinsp;0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e\u0026minus;\u0026thinsp;0,3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u0026thinsp;0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e+\u0026thinsp;0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e+\u0026thinsp;0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e+\u0026thinsp;0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e+\u0026thinsp;0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e+\u0026thinsp;0,04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003e\u003csup\u003e1. Pheniramine\u0026minus;Dexamethasone, 2. Diclofenac\u0026minus;Metoclopramide, 3. Hyoscine\u0026minus;N\u0026minus;butylbromide\u0026minus;Pulcet, 4. Metoclopramide\u0026minus;Progas\u003c/sup\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe greatest pH differences were observed as follows: for pheniramine-dexamethasone between the 10th and 60th minutes (+\u0026thinsp;0.19), for diclofenac-metoclopramide between the 0th and 60th minutes (+\u0026thinsp;0.21), for hyoscine-N-butylbromide-Pulcet between the 0th and 60th minutes and the 15th and 60th minutes (-0.3), and for metoclopramide-Progas between the 0th and 10th minutes and the 0th and 15th minutes (-0.08).\u003c/p\u003e \u003cp\u003eAt wavelengths of 350, 400, and 550 nm, the maximum change within one hour was 0.01 for pheniramine-dexamethasone, 1.89 for diclofenac-metoclopramide, 0.14 for buscopan-pantoprazole, and 0.03 for metoclopramide-pantoprazole (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOptical density values of the mixtures at different wavelengths\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e350 nm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e400 nm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003e550 nm\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixture\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ediff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ediff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ediff\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePheniramine\u003c/p\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eDiclofenac Metoclopramide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2,23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2,15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1,78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2,22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2,14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1,69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2,21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1,76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,42\u003c/p\u003e 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\u003cp\u003e0,14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMetoclopramide\u003c/p\u003e \u003cp\u003eProgas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0,08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0,02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0,07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0,09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0,02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhen examined with the naked eye, a colour change was observed only in the diclofenac-metoclopramide mixture. At the moment the two drugs were mixed, the colour turned white. Since this indicates a failure to meet one of the conditions for physical compatibility, emergency physicians should avoid preparing this mixture in routine practice. Additionally, as no more than 3 mL of medication should be administered in a single IM injection to a well-developed adult [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] the resulting mixture (5 mL) exceeds the recommended volume. To prevent tissue damage, attention should be paid not only to physical incompatibility but also to this volume issue. Another example that should be noted in this context is the diclofenac-thiocolchicoside mixture (3\u0026thinsp;+\u0026thinsp;2\u0026thinsp;=\u0026thinsp;5 mL), which is commonly used in our emergency departments. In the IV compatibility section of Clinical Pharmacology powered by ClinicalKey [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], it is stated that diclofenac and thiocolchicoside are compatible when mixed in the same syringe. However, in UpToDate Lexidrug [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], no selectable option appears when searching for thiocolchicoside to evaluate incompatibility. Similarly, the Micromedex IV compatibility [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] assessment does not provide any results for this combination. Furthermore, the outdated reference provided by Clinical Pharmacology for this mixture suggests the need for further evaluation.\u003c/p\u003e \u003cp\u003eYellowing was observed in the solutions containing pantoprazole after one day; however, it could not be determined whether this was due to IV incompatibility or the duration for which pantoprazole remains stable in solution (incompatibility versus instability). The product label includes the following information: \u0026ldquo;The product must be used immediately from a microbiological perspective. If not used immediately, the storage duration and conditions during use are the responsibility of the user, and this period should not normally exceed 12 hours at 25\u0026deg;C.\u0026rdquo; Another noteworthy point in our study is that, due to updates made at different times to the usage instructions of different pantoprazole preparations, one of the preparations we used states: \u0026ldquo;Stable for 12 hours at 25\u0026deg;C after reconstitution and dilution with the following solutions: Reconstitution with 10 mL of 0.9% NaCl solution; reconstitution with 10 mL of 0.9% NaCl solution followed by dilution with 100 mL of 0.9% NaCl solution; reconstitution with 10 mL of 0.9% NaCl solution followed by dilution with 100 mL of 5% dextrose solution.\u0026rdquo; However, with a recent update this year, this section has been revised to: \u0026ldquo;Stable for 12 hours at 25\u0026deg;C after reconstitution and dilution.\u0026rdquo; [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The new update is more practical and less confusing because it eliminates the possibility that users might assume issues only arise with specific mixtures listed and that there is no data available for other combinations.\u003c/p\u003e \u003cp\u003eWhen examining the changes in OD values within 1 hour, the values for pheniramine-dexamethasone showed almost no variation across all three mixtures. Therefore, this mixture was considered compatible. In contrast, the OD values for diclofenac-metoclopramide exhibited changes of up to 1.89, which was an expected outcome due to the visible changes observed with the naked eye. For buscopan-pantoprazole, the maximum change was found to be 0.14; however, this change was observed in only one well, while the maximum changes in the other two wells were 0.01 and 0.02. Thus, no definitive conclusion could be drawn. The same situation was observed for the metoclopramide-pantoprazole mixture.\u003c/p\u003e \u003cp\u003eConsidering previous guidelines and studies, the changes in pH values within the examined time intervals were too small to be considered significant. Given that pH changes during the first 20 minutes were minimal and that medications are typically administered within a relatively short time in emergency department practice, no incompatibility could be identified based on pH evaluation. However, potential scenarios, such as the need to prepare medications in advance due to the workload in emergency departments or delays in administration for other reasons, should not be overlooked.\u003c/p\u003e \u003cp\u003eAs with other studies utilizing biochemical methods, it would be beneficial to re-evaluate the drugs examined in this study. Another factor necessitating the repetition of incompatibility studies is the potential role of excipients in interactions. Brousseau et al. reported that when they began sourcing dexamethasone from a new supplier, precipitation occurred in mixtures prepared with the new formulation, unlike with the previous one [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the formulation obtained from the previous supplier, methylparaben/propylparaben were used as preservatives, whereas benzyl alcohol was used in the preparation from the new supplier. To assist future studies, incompatibility studies should also specify the excipients present in the formulations. In our study, the excipients for the drugs used were as follows: for metoclopramide, sodium chloride, sodium metabisulfite, and distilled water; for pheniramine, water for injection; for dexamethasone, creatinine, phenol, sodium citrate dihydrate, sodium hydroxide, sodium metabisulfite, and water for injection; for diclofenac, mannitol, sodium metabisulfite, benzyl alcohol, propylene glycol, sodium hydroxide, and water for injection; for pantoprazole (Progas), sodium hydroxide and water for injection; and for pantoprazole (Pulcet), disodium EDTA and sodium hydroxide. When evaluating incompatibility in clinical practice or examining interaction results, these details should also be compared as much as possible. In addition to the active ingredient, information on preservatives and carriers (e.g., pockets or syringes) as well as materials (e.g., polypropylene) can also be found in resources such as Th\u0026eacute;riaque, where these factors can be selected and analyzed. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. To improve or expand these resources, the materials used, as well as excipients, should be specified and compared when necessary in clinical practice.\u003c/p\u003e \u003cp\u003eIn our study, pheniramine and dexamethasone were sequentially added to saline using separate syringes. This approach was taken because the dosage of drugs is a critical factor in IV incompatibility, and one of the reasons syringe compatibility and solution compatibility are distinct scenarios. However, if the practitioner uses the same syringe to draw drugs directly from ampoules/vials, this could lead to different outcomes. Therefore, if data on syringe compatibility are available, it may be beneficial to consider them as well.\u003c/p\u003e \u003cp\u003eThis study focused on the physical compatibility of the drugs. While pH evaluation is part of chemical compatibility assessment, it alone is insufficient to determine whether two mixtures are compatible. Chemical evaluation requires more advanced and extensive analyses (e.g., HPLC, LC/GC-MS). Nevertheless, any mixtures showing evidence of physical or chemical incompatibility should be avoided in clinical use. Additional studies are required to make mixtures that appear compatible more applicable in clinical practice. Pharmacopoeia methods and the minimum requirements outlined in the guideline prepared following the European Consensus Conference [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] should be taken into consideration in studies; however, it is beneficial to utilize as many methods as possible.\u003c/p\u003e \u003cp\u003eHealthcare professionals need to learn which resources they can use for information on IV incompatibility. When choosing among these resources, they should identify the differences between them and determine which one is most suitable for their practice. They should also be able to consult with a clinical pharmacologist or pharmacist about potential mixtures for which they cannot find data or wish to learn more.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funds, grants, or other support was received.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailable upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions of Authors statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAO designed the study. AO: performing experiments, data analyses, writing the original draft. ZEYD: support on performing experiments and review of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMaison O, Tardy C, Cabelguenne D, et al (2019) Drug incompatibilities in intravenous therapy: evaluation and proposition of preventive tools in intensive care and hematology units. Eur J Clin Pharmacol 75:179\u0026ndash;187. https://doi.org/10.1007/s00228-018-2602-6\u003c/li\u003e\n \u003cli\u003eMarsilio NR, Silva D da, Bueno D (2016) Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva 28:147\u0026ndash;153. https://doi.org/10.5935/0103-507X.20160029\u003c/li\u003e\n \u003cli\u003eStabilis 4.0. https://www.stabilis.org/. Accessed 2 Sep 2024\u003c/li\u003e\n \u003cli\u003eSriram S, Aishwarya S, Moithu A, et al (2020) Intravenous Drug Incompatibilities in the Intensive Care Unit of a Tertiary Care Hospital in India: Are they Preventable? J Res Pharm Pract 9:106. https://doi.org/10.4103/jrpp.JRPP_20_11\u003c/li\u003e\n \u003cli\u003eBardin C, Astier A, Vulto A, et al (2011) Guidelines for the practical stability studies of anticancer drugs: A European consensus conference. Ann Pharm Fr 69:221\u0026ndash;231. https://doi.org/10.1016/j.pharma.2011.07.002\u003c/li\u003e\n \u003cli\u003eCruz KCE, Churchwell MD, Mauro VF, Boddu SHS (2018) Physical compatibility of levetiracetam injection with heparin, dobutamine, and dopamine. Am J Health-Syst Pharm AJHP Off J Am Soc Health-Syst Pharm 75:510\u0026ndash;512. https://doi.org/10.2146/ajhp180069\u003c/li\u003e\n \u003cli\u003eYoussef SH, Garg A, Song Y, et al (2024) Harmonising IV Oxycodone with Paediatric Perioperative Medications: A Compatibility Study Through Y-Type Connectors. Drug Des Devel Ther 18:899\u0026ndash;908. https://doi.org/10.2147/DDDT.S444581\u003c/li\u003e\n \u003cli\u003eYliruusi JK, Sothmann AG, Laine RH, et al (1982) Sorptive loss of diazepam and nitroglycerin from solutions to three types of containers. Am J Hosp Pharm 39:1018\u0026ndash;1021\u003c/li\u003e\n \u003cli\u003eElsevier (2024) Medication Administration: Intramuscular Injections - Acute care. In: Medicat. Adm. Intramuscular Inject. - Acute Care. https://elsevier.health/en-US/preview/intramuscular-injections-acute-care. Accessed 21 Aug 2024\u003c/li\u003e\n \u003cli\u003eClinical Pharmacology powered by ClinicalKey | Elsevier. In: www.elsevier.com. https://www.elsevier.com/products/clinicalkey/clinical-pharmacology. Accessed 10 Oct 2024\u003c/li\u003e\n \u003cli\u003eUpToDate Lexidrug. https://online.lexi.com/. Accessed 10 Oct 2024\u003c/li\u003e\n \u003cli\u003eMicromedex. https://www.micromedexsolutions.com/home/dispatch/. Accessed 10 Oct 2024\u003c/li\u003e\n \u003cli\u003eK\u0026uuml;b/Kt Listesi. https://www.titck.gov.tr/kubkt. Accessed 10 Oct 2024\u003c/li\u003e\n \u003cli\u003eBrousseau P, Nickerson J, Dobson G (2007) Dexamethasone and ondansetron incompatibility in polypropylene syringes. Can J Anesth 54:953\u0026ndash;954. https://doi.org/10.1007/BF03026805\u003c/li\u003e\n \u003cli\u003eTh\u0026eacute;riaque. https://www.theriaque.org/apps/contenu/journal.php?menu=4. Accessed 2 Sep 2024\u003cu\u003e\u003c/u\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Intravenous incompatibility, pharmaceutical interactions, emergency medicine, drug safety","lastPublishedDoi":"10.21203/rs.3.rs-5566976/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5566976/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e The study investigates the physicochemical compatibility of four drug mixtures commonly used in emergency departments. It aims to address the limited data on intravenous incompatibilities and to enhance clinical practice by identifying potential risks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eMixtures of pheniramine-dexamethasone, diclofenac-metoclopramide, hyoscine-N-butylbromide-pantoprazole, and metoclopramide-pantoprazole were prepared under simulated emergency department conditions. pH changes were measured at multiple time points (0–60 minutes), and optical density was assessed using a spectrophotometer at specified wavelengths. Visual inspections were conducted immediately after preparation and at regular intervals to detect colour changes, turbidity, precipitation, and gas formation. Compatibility evaluation integrated all these parameters to provide a comprehensive assessment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe diclofenac-metoclopramide mixture exhibited visible turbidity and significant optical density changes (up to 1.89), indicating physical incompatibility. Yellowing was observed in pantoprazole-containing mixtures after 24 hours, raising concerns about stability or incompatibility. Minimal pH changes were recorded across all mixtures, with the largest difference being ±0.3 units. Pheniramine-dexamethasone demonstrated high stability with negligible optical density variations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe diclofenac-metoclopramide mixture is unsuitable for clinical use due to physical incompatibility. Pantoprazole-containing mixtures require further investigation. This study highlights the need for comprehensive compatibility data and recommends cautious use of empirically prepared drug mixtures in emergency settings.\u003c/p\u003e","manuscriptTitle":"Physicochemical Compatibilities: Analyzing Aspects in Four Different Mixtures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 05:57:32","doi":"10.21203/rs.3.rs-5566976/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90cc9cca-272c-45b6-bd26-692e3bf88462","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-17T05:57:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-17 05:57:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5566976","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5566976","identity":"rs-5566976","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}