Semisolid Products Research Articles

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence.

Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from ±10% to ±20%/±25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches.

Complying with the Guideline for Quality and Equivalence for Topical Semisolid Products: The Case of Clotrimazole Cream.

Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A “quality by design” approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved.

Pegaruh Penambahan Sari Wortel Terhadap Pembuatan Yogurt ditinjau dari fisik kimia dan organoleptik

Yoghurt was one form of beverage products from milk processing that utilizes microbes in the fermentation of fresh milk into a semi-solid emulsion product with a more acidic taste. The aim of this research was to know the effect of carrot juice and optimal addition were: color, organoleptic quality (aroma, texture, color and taste), vitamin C, WHC of yoghurt. The materials used were fresh milk, carrot juice, starter plain yoghurt. The method used in this research is experimental method with Randomized Completely Block Design of 5 treatments namely the addition of carrot juice in yoghurt with concentration 0%, 10%, 15%, 20%, and 25% of milk volume (1000 ml), with each treatment was done with 4 blocks. The data analysis used variance analysis, followed by Duncan Multiple Range Test. The results showed that the addition of carrot juice 20% in the manufacture of yoghurt with different concentrations gave a very significant effect difference (P<0.01) on the lightness (L*), yellowness (b*), vitamin C and WHC as well as a real effect (P <0,05) to the redness color (a*) and not not give significant effect (P>0,05) to pH, syneresis and lactic acid bacteria. The result showed that the concentration of adding carrot juice is 20%, which results in the best quality yogurt drink with the following average values of vitamin C; 15.13%, color; 59.95 (L), 19.30 (a *), 25.85 (b *), WHC; 25% and organoleptic; 3.75 (aroma), 3.98 (color), 3.40 (taste) 4.44 (texture), pH; 4.75Keyword: carrot juice, physical quality, yoghurt

A simple method to predict transient diffusion processes in ellipsoids

This work is focused on transient diffusion processes inside semi-solid and solid agri-food products presenting ellipsoidal shape, i.e. prolate and oblate spheroids and general ellipsoid. Many typical industrial operations like drying, soaking, rehydration, heating, cooking, and cooling, can be effectively modelled by using Fick's law for mass diffusion and Fourier's law for heat conduction, with constant properties and neglecting volume/shape variations. To predict such processes, there are some methods available in the literature, although they are limited to certain shapes and/or operating conditions and their implementation can be quite complicated. Therefore, our objective was to develop a simple method to predict transient diffusion processes in ellipsoids and spheroids, considering both local and average values of industrial interest. The methodology to obtain such a simple method consisted in first generating numerical data by simulating a wide range of shapes and conditions, and then fitting a simple two-parameter expression, which is based on the analytical solution for regular geometries. The developed method can be easily implemented through the use of tabulated values provided in this article. Finally, the capability of the proposed method was verified by using previously reported data, showing very good results and demonstrating that it is easily implementable. It is expected that the developed simple method can be helpful for industrial applications and to improve calculations in related fields of research, which may not be familiar with transport phenomena modelling. • Many food processes involve transient mass and/or heat diffusion in ellipsoids. • A semi-analytical, user-friendly and accurate prediction method is developed. • Different prolate, oblate and general ellipsoids, and Biot values are covered. • Evolution of average, central and surface values of dependent variable is predicted. • The simple method can also estimate transport properties by inverse methodology.

Advanced Formulation Design for Topical Creams Assisted with Vibrational Spectroscopic Imaging.

Vibrational spectroscopic imaging has become useful analytical tools for quality control of drug products. In this study, we applied microscopic attenuated total reflection (ATR)-IR and confocal Raman microscopy to elucidate microscopic structure of creams and for the formulation design in the development of semi-solid drug products. The model creams were prepared with prednisolone (PRD) and fluconazole (FLC) as active pharmaceutical ingredients and oily solvents such as mineral oil (MO), isopropyl myristate (IPM), benzyl alcohol (BA) and diethyl sebacate (DES). As a result of microscopic ATR-IR imaging, several domains indicating oily internal phase were observed, which had absorption around 1732 and 1734 cm-1 derived from MO, IPM and DES. In addition, domains of BA around 1009 cm-1 were observed at the complemental or similar position in the formulation with MO or DES, respectively. These results suggested that the creams were oil-in-water type and the distribution of domains would reflect the compatibility of the solvents. The contents of PRD and BA were determined quantitatively in each layer after the intentional separation of the creams and the results agreed well with the imaging analysis. Whereas, confocal Raman imaging allowed to visualize the distribution of the components in depth direction as well as two-dimensional plane. In particular, the Raman imaging would ensure the coexistence of FLC and BA as oily phase in the cream. From these results, the feasibility of spectroscopic imaging techniques was successfully demonstrated for the formulation design of semi-solid dosage forms.

Effect of surfactant on quality and performance attributes of topical semisolids

Surfactants are the most common inactive ingredients used in topical drug products. Surfactants in topical products play many functional roles such as emulsifiers, permeation enhancers, and solubilizers. This study was aimed to evaluate the influence of incremental change in the concentration of a surfactant (tween 80) on the quality attributes and performance of semisolid topical products. Four creams were prepared using metronidazole as a model drug using the same manufacturing protocol and similar composition except for the concentration of tween 80, which was increased by 5% w/w across SF1 to SF4. The quality attributes like globule size, pH, drying rate, and in-vitro permeation profile were characterized. The critical quality attributes did not differ significantly across the products. However, there was a significant difference in the permeation profile of the products. The permeation flux (Jmax) varied from SF1 to SF4 (51.25 ± 35.29 to 307.98 ± 138.89 ng/cm2/h, respectively). The reason for the difference in the performance of products despite having consistent quality attributes was investigated. One of the major reasons was found to be the difference in the time course of degree of saturation of drug during the evaporative metamorphosis. This study confirms that the time course of degree of saturation is one of the important quality attributes of the topical product that could influence bioavailability and performance of topical products.

The Design of Experiment Approach, Rheology for Optimization of a Topical Anti-inflammatory and Analgesic Cream.

A capsaicin cream was formulated by optimizing the rheological stability, the release behavior of the drug, and the pharmacological effect. This study aimed to: (a) apply the Design of Experiment approach to study the rheological stability and release behaviors of a drug (capsaicin) from a formulated oil-in-water cream and (b) investigate the skin irritation and anti-inflammatory and analgesic effects of the optimized cream. The cream prepared by the emulsification method was optimized using the central composite design, and then the pharmacological effect in experimental animals was determined using Complete Freund's adjuvant (CFA). The effects of a permeation enhancer (X1), Vaseline (X2), and surfactants (X3) on the fluctuation of the ratio of the viscous modulus (G ') to elastic modulus (G') (tan δ) after three cycles of cooling-heating (10-40°C), flux, and skin deposition of capsaicin after 8 h on mouse skin were statistically analyzed and optimized. The final obtained CAP-cream did not cause irritation in the rabbit model and produced comparable anti-inflammatory and analgesic effects to the reference product (Voltaren® emulgel). This study successfully integrated the DoE approach, rheological science, and pharmacological studies to develop a stable and highly effective semi-solid product containing capsaicin.

Influence of Inter- and Intra-Batch Variability on the Sample Size Required for Demonstration of Equivalent Microstructure of Semisolid Dosage Forms

Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar microstructure of the semisolid. This investigation shows that the minimum number of batches to be compared of each product is 3 and the minimum number of units per batch could be 6 in the case of low intra- and inter-batch variability. If the products are not identical, i.e., 2.5–5% differences that are expected due to differences in the manufacturing process or the suppliers of excipients, 12 units and 6 batches are needed. If intra- or inter-batch variability is larger than 10%, the number of batches and/or the number of units needs to be increased. As the interplay between inter- and intra-batch variability is complex, the sample size required for each combination of inter- and intra-batch variability and expected difference between products can be obtained in the attached tables.

Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck.

Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products. For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability. Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences. Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products. Graphical abstract.

A Rapid Tool to Optimize Process Variables for Continuous Manufacturing of Metronidazole Ointment Using Melt Extrusion Technique.

The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important. In this study, a handheld colorimeter has been explored to optimize the process variables of twin screw processor for preparation of hydrophilic PEG-based ointment. The process parameters which were optimized with use of handheld colorimeter have been used for preparation of polyethylene glycol-based metronidazole ointment. The metronidazole ointment prepared by twin screw processor was compared with commercially available metronidazole gel for in vitro release testing and ex vivo permeation. The flux, ex vivo bioavailability, and Tmax of polyethylene glycol-based metronidazole ointment was found to be similar to that of marketed metronidazole gel.

In Vitro Permeation Test (IVPT) for Pharmacokinetic Assessment of Topical Dermatological Formulations.

In vitro assessment of topical (dermal) pharmacokinetics is a critical aspect of the drug development process for semi-solid products (e.g., solutions, foams, sprays, creams, gels, lotions, ointments), allowing for informed selection of new chemical entities, optimization of prototype formulations during the nonclinical stage, and determination of bioequivalence of generics. It can also serve as a tool to further understand the impact of different excipients on drug delivery, product quality, and formulation microstructure when used in parallel with other techniques, such as analyses of rheology, viscosity, microscopic characteristics, release rate, particle size, and oil droplet size distribution. The in vitro permeation test (IVPT), also known as in vitro skin penetration/permeation test, typically uses ex vivo human skin in conjunction with diffusion cells, such as Franz (or vertical) or Bronaugh (or flow-through) diffusion cells, and is the technique of choice for dermal pharmacokinetics assessment. Successful execution of the IVPT also involves the development and use of fit-for-purpose bioanalytical methods and procedures. The protocols described herein provide detailed steps for execution of the IVPT utilizing flow-through diffusion cells and for key aspects of the development of a liquid chromatography-tandem mass spectrometry method intended for analysis of the generated samples (epidermis, dermis, and receptor solution). © 2020 Wiley Periodicals LLC. Basic Protocol 1: In vitro permeation test Support Protocol: Dermatoming of ex vivo human skin Basic Protocol 2: Bioanalytical methodology in the context of the in vitro permeation test.

Dynamic texture perception in plant-based yogurt alternatives: Identifying temporal drivers of liking by TDS

As texture properties in novel food categories have a crucial role in consumer acceptance, mouthfeel profile of different plant-based yogurt-like semi-solid products were studied and compared to dairy yogurts. Mouthfeel properties of five plant-based yogurt-like products and two dairy yogurts were analyzed using temporal dominance of sensations (TDS) with consumers (n = 87). The attributes evaluated were thick, thin, creamy, watery, sticky, and foamy. Following TDS, overall liking and mouthfeel liking were evaluated using a 7-point hedonic scale. Temporal drivers of mouthfeel liking were studied using correspondence analysis and penalty-lift analysis with different time points during mastication. For penalty-lift analysis TDS data was analyzed as check-all-that-apply (CATA) data. Results from the present work show that mouthfeel perception in non-dairy yogurt alternatives is a dynamic process. Attributes typically used to describe dairy yogurts are also relevant for describing non-dairy yogurt alternatives. Yogurt alternatives and dairy yogurts can be similar and equally liked by their mouthfeel profile. Temporal drivers of liking in plant-based products are thickness and creaminess and temporal drivers of disliking are thinness and wateriness. In this study, the first dominant attributes were found to have a stronger impact on mouthfeel liking than the dominant attributes perceived later during mastication.

Thermochemical conversion of birch bark by temperature-programmed slow pyrolysis with fractional condensation

Pyrolysis is a promising method for thermochemical conversion of forest biomass into liquid biofuels or platform/specialty chemicals. In this work, bark from silver birch (Betula pendula) was processed through slow pyrolysis with fractional condensation, and the obtained liquid fractions were analyzed by various bulk chemical analyses as well as high-resolution mass spectrometry. The process had three successive stages, drying, torrefaction, and pyrolysis, occurring at 135, 275, and 350 °C, respectively, and pyrolysis liquids were obtained at three condensing temperatures, 130, 70, and 5°C, resulting in eight liquid fractions. Most fractions had high water content, especially those obtained from the drying stage. Only the semi-solid product, obtained from the pyrolysis stage at the condensing temperature of 70°C, had a very low water content and a high carbon yield. There were major differences in the chemical compositions between the liquid fractions; the drying fractions contained mostly aliphatic and phenolic extractives as well as light hydrocarbons, while the torrefaction fractions were enriched with sugaric compounds, resulting from hemicellulose and cellulose degradation. In contrast, the pyrolysis fractions were mainly composed of suberinic fatty acids, terpenoids (e.g., betulin) and their condensation products, and phenolic compounds. Many terpenoids were dehydrated to form a plethora of condensed, water-insoluble alicyclic and aromatic hydrocarbons. Although the temperature-programmed slow pyrolysis shows potential for thermochemical processing of industrial bark residues, excessive dehydration reactions may limit its applicability especially for “in situ fractionation”.

Production of modified bitumen from used engine oil, coal tar and waste tyre for construction applications

Bitumen plays an important role especially in the community in terms of infrastructure where its properties are utilized. It is a semi-solid hydrocarbon product which is produced by removing the lighter fractions such as liquid petroleum gas from heavy crude oil during the refinery processes of crude oil. It consists of a mixture of organic liquids and it has a black colour, high viscosity and it is a sticky material. The most common method for its manufacture is fractional distillation of atmospheric residue from vacuum distillation where waxy distillates are used. To reduce the expenses for its production from crude petroleum, used engine oil, coal tar and used tyres from automobiles can be used in their correct ratio to produce bitumen. The process involves heating and mixing using a high-speed shear mixer. The oil is a medium to heat and melt the crumb rubber so that it will begin to degrade (depolymerize). Several key tests as per ASTM standards were performed to check if the bitumen was up to standard, and these included: (i) viscosity, (ii) specific gravity, (iii) softening point, (iv) thin film test, (v) flash point and (vi) fire point. The best formulated bitumen had a ratio of 20% engine oil, 50% crumb rubber and 30% coal tar with a viscosity of 93 cP, a specific density of 1.089, a softening point temperature of 65°C, thin film oven test of 0.35% mass loss, a flash point temperature of 218°C and a fire point temperature of 223°C. This bitumen showed better resistance to permanent deformation but less resistance to fatigue cracking, was less susceptible to temperature change meaning it could withstand hot climates, had less volatiles to give off and was a lower fire hazard.

PENAMBAHAN PENAMBAHAN PEKTIN, GULA, DAN ASAM SITRAT DALAM PEMBUATAN SELAI DAN MARMALADE BUAH-BUAHAN

Quality degradation due to the process of respiration as well as physical, chemical and biological damage to the fruit is very undesirable because it caused indirectly shorten the shelf life of the fruit. Damaged fruit will have a low selling value. Various attempts were made to overcome these problems including of fruit chips, sweets, to fruit leather. In addition to these methods, fruit can also be processed into bread spread ingredients such as jam and marmalade. Jam is a thick or semi-solid food product made from crushed or chopped of fruit with added some sugar. Marmalade is a semi-solid food product made from fruit juice, sugar, citric acid, and includes pieces of fruit or fruit skin. Marmalade is generally made from citrus fruits, but nowadays marmalades are also made from other fruits. Both of jam and marmalade products involve the heating process and the use of high concentrations of sugar as a preservative. Several factors that influence the making of jam and marmalade include pectin, sugar, water and the presence of acids which are very influential in gel formation.

The dynamics of starch hydrolysis and thickness perception during oral processing

While it is known that salivary amylase changes perceived thickness in starch-based foods, the dynamics of oral breakdown of starch has not been related to that of sensory perception. This work examines the associations between in-mouth oral breakdown of starch by α-amylase and thickness of a semisolid product measured instrumentally and using a sensory panel. Pureed carrots made with added waxy maize (w/w) (0% (control), 0.4% (S0.4) and 0.8% (S0.8)), were tested for dilution and hydrolysis effects with the addition of water and saliva and measuring viscosity (shear of 10 s−1), viscoelasticity (10–0.01 Hz at 0.1% strain) and maltose release. Sensory testing was conducted using progressive profiling. Control and S0.8 pureed carrots showed similar viscosities at 10 s−1 while S0.4 was lower. Addition of saliva had the highest impact on viscosity drop for S0.8. Viscoelastic properties of pureed carrots decreased with starch addition which decreased further with water/saliva incorporation. Starch breakdown measured in terms of maltose release did not change with starch concentration and oral processing times. Unlike instrumental viscosity results, perceived thickness of purees increased with starch concentration. During oral processing, thickness decreased at a constant rate across all samples highlighting the dilution effect of saliva. A relation was observed only between oral viscosity and starch hydrolysis and not rheological measurements. This indicates that changes in starch hydrolysis during oral processing can be used as an indicator of rate of drop in perceived viscosity in starch-based semi-solid foods such as pureed carrots.

Quality by Design: Development of the Quality Target Product Profile (QTPP) for Semisolid Topical Products.

In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the quality target product profile (QTPP), a list of quality attributes (QAs) that are required to be present in the final product. These quality attributes are affected by the ingredients used as well as manufacturing procedure parameters. Hence, critical material attributes (CMAs) and critical process parameters (CPPs) need to be specified. Possible failure modes of a topical semisolid product can be determined based on the physiochemical properties of ingredients and manufacturing procedures. In this review, we have defined and specified QTPP, QAs, CMAs and CPPs that are required for developing a topical semisolid product based on the QbD approach.

A novel low-alkali konjac gel induced by ethanol to modulate sodium release

Alcogels have attracted many attentions recently due to their versatile functions and potential applications in developing innovative semi-solid alcohol-containing products. In this study, comparisons were made in the aspect of rheology, physicochemical properties and sodium release between the conventional alkali konjac glucomannan (KGM) gels and alkali KGM alcogels prepared by mixing ethanol with KGM aqueous solution at 0.02 wt%, 0.04 wt% or 0.08 wt% Na2CO3. 20% (v/w) Ethanol could promote the formation of a rigid yet brittle alcogel of KGM with lower dependence of rheological response on frequency and temperature at as low as 0.02 wt% Na2CO3. KGM alcogels were more opaque and constructed by small highly-connected pores, which are 30% smaller in average than those of their counterparts, examined by turbidity and microstructure measurements. Although the swelling ratio of KGM alcogel was only about one third of that of conventional alkali-induced gel, there was about fourfold rise in the amount of Na+ released from alcogels. The release of Na+ could be probably regulated by fine-tuning the macro-properties of alcogels through controlling the alkali concentrations.

Safe-by-design development of a topical patch for drug delivery

Few topical products have been developed specifically to treat acute and chronic arthritis and inflammation, using non-steroidal anti-inflammatory drugs (NSAIDs). The lack of dosing accuracy commonly found in locally applied semisolid products for cutaneous use is a critical issue that leads to treatment failure. The aim of the present work is to develop a differentiated and innovative topical patch based on a monolithic hydrogel for ibuprofen skin delivery, in order to provide a safer and accurate way of drug administration along with improved treatment compliance. Topical patches based on hydroxypropylmethylcellulose (HPMC) were optimized in composition, in terms of enhancer and adhesive, supported on a systematic assessment of in vitro release and permeation behavior and adhesion properties. Several mathematical models were used to scrutinize the release mechanisms from the patches. In vitro release kinetics was shown to be mainly driven by diffusion. However, other mechanisms seemed to be also present, supporting the feasibility of using patches for sustained drug delivery. PEG 200 provided the best permeation rate, with a permeation enhancement ratio of ca. 3 times higher, than the commercial reference. The addition of Eudragit L30D 55 to the formulation led to the best adhesion profile, thus achieving a successful development based on a safe-by-design concept.

Antimikrobiyal Aktivitenin Belirlenmesinde Cross-Streak Metodu Kullanımı

Antimikrobiyal duyarlılık testleri, ilaçların keşfedilmesi, epidemiyoloji ve terapötik sonuçların tahmini için kullanılabilmektedir. Günümüzde mikrobiyal yaşamdaki dirençlilik artış göstermekte olduğu için antimikrobiyal bileşikler etkilerini kaybetmekte ve bu durum onları tehlikeye sokmaktadır. Ayrıca, antimikrobiyal ajanların etkileri, çoklu ilaca dirençli bakterilerle ilişkili tedavilerde başarısızlık göstermektedir. Bu durum, halk sağlığı için küresel bir endişe olma durumuna gelmiştir. Bu yüzden, yeni antimikrobiyal ajanların keşfedilmesi ve antimikrobiyal duyarlılık testlerinin yaygın olarak kullanılması ve geliştirilmesi gerekmektedir. Antimiktobiyal aktivitenin belirlenmesi için birçok teknik bulunmaktadır. Duyarlı mikroorganizmaları inhibe etmek amacıyla uygulanan bu tekniklerden çoğu, katı ya da yarı katı üretim ortamındaki difüzyon ile ilişkili metodlara dayalıdır. Bu teknikler arasında Cross-streak ise yeni antibiyotik keşfi için yapılan araştırmalarda kültürlerin nispeten hızlı bir şekilde taranmasını sağlayan kolay bir tekniktir. Fakat Cross-streak testinin en büyük dezavantajı, niceliksel verilerin elde edilmesindeki güçlüktür. Çünkü inhibisyon bölgesinin kenarları genellikle çok bulanık ve belirsizdir. Bazı antimikrobiyal duyarlılık test teknikleri, bu alandaki dikkat çekici adımlar belirlenerek Clinical Laboratory Standards Institute (CLSI) ve European Committee on Antimicrobial Susceptibility Testing (EUCAST) tarafından standardizasyona tabi tutulmuştur. Bu test prosedürü, spesifik test koşullarının ve metotlarının kullanımına gereksinim duymaktadır. Ayrıca, besiyeri ve inkübasyon koşulları ile zaman bu gereksinimler arasındadır. Hali hazırda kullanılan aktivite belirleme yöntemlerinden Cross-streak yönteminin iyi anlaşılıp geliştirilmesi önem arz etmektedir.