Chemical Product Engineering: Research and Educational Challenges

0263–87862/02/$10.00+0.00 # Institution of Chemical Engineers Trans IChemE, Vol 80, Part A, January 2002

CHEMICAL PRODUCT ENGINEERING: RESEARCH AND EDUCATIONAL CHALLENGES E. FAVRE 1 , L. MARCHAL-HEUSLER 1 and M. KIND2 1 Groupe ENSIC, INPL, Nancy, France. Institut fu¨r Thermische Verfahrenstechnik, Universita¨t Kalrsruhe, Germany.

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hemical engineering has a long tradition and proven methodology of process design with emphasis on commodity chemicals (large quantity, continuous production of low added-value molecules). Nevertheless the chemical industries nowadays are increasingly involved in specialty chemicals (small quantity, batch production, high added value) as well as formulated products (complex mixtures targeted to confer speciŽ c end-use properties). In addition to process design and optimization which are the major concerns of commodity production, the specialty and formulated product industries face also new technical as well as marketing challenges (time to market, smart product design, choice or adaptation of generic, not dedicated plants etc.). Moreover, in place of the classical unit operations found in commodity production (distillation, absorption, extraction etc.), more exotic operations such as emulsiŽ cation, spray cooling, extrusion, coating and granulation are relevant to formulated product elaboration. This situation calls for an examination of the possibilities and limitations of chemical engineering methodology within a product oriented framework. After a short historical overview of chemical product industry, this paper tentatively identiŽ es some of the actual and future challenges of what is termed chemical product engineering, from the research and education points of view. Keywords: product; engineering; formulation; processes; education; specialties.

INTRODUCTION

enduring market driven movement of CPI began decades ago. It led to an increased percentage of activities oriented towards specialty products (such as polymers, surfactants, pigments and  avours). More than 50% of the market of CPI is currently made up of specialty chemicals. Major differences between these two types of chemicals have been clearly highlighted in the Amundson report2. For instance, while product price is the major concern in the Ž eld of commodity chemicals, quality and performance are more important in the area of speciality chemicals. Another major trend in the Ž eld of CPIs is worth mentioning at this stage. Companies were used originally to developing their identity around chemical concepts (such as ammonia, phenol, aniline or sulfur compounds production) whereas today the paradigm has completely changed with product properties (i.e. from the consumer viewpoint) acting as the major criterion of the industrial strategy of business units (e.g. fertilisers, detergents, drugs, antifoams). CPIs are no longer subdivided according to what chemicals they intrinsically produce, but rather by the end-use properties of their products. Another enduring trend in CPIs is to provide the customers not only with a chemical in the strictest sense of the term, but with a product. Individual substances are no longer able to meet the ever increasing demands of customers. Instead, molecular systems are tailored to meet speciŽ c purposes, the so called end-use

Historical Perspective The Ages of Industrial Chemistry Based on a Product Approach Empirical process engineering activities started many centuries ago and were exclusively concerned with the puriŽ cation or chemical transformation of natural products. Metallurgy, and to a lesser extent glass and sodium chloride production remained the major activities for a long time. Figure 1 shows an example of the techniques used in the Ž eld of iron productionfrom what is considered as the Ž rst encyclopaedia of process technology, written by G. Agricola in 15561. New production processes mainly for the transformation of ore into mineral compounds appeared at the end of the 18th century (acids, bases, salts). Another breakthrough followed, about one century later, with the development of organic synthesis, leading to covalently bonded carbon compounds, obtained Ž rst from coal (carbochemistry), and later from oil (petrochemistry). This period coincided with the emergence of industrial chemistry and the exponential growth of chemical process industries (CPIs). Nowadays, more than 107 chemical compounds are known and about 105 can be found on the market. Apart from the production of so-called commodity chemicals (ammonia, sulfuric acid, methanol, ethylene), a slow but 65

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Figure 1. Product engineering in the early ages: processing of iron in the 15th century according to G. Agricola1.

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properties3. Typically, 4 to 50 components (i.e. molecules) can be found in a formulation or grade. The generic term of formulated product is classically used to cover the large body of industrial sectors which are involved in this type of production (paints, cosmetics, inks, pharmaceutical, personal care, household, food). A brief classiŽ cation of formulated products according to their state of matter is shown in Table 1 with illustrations from different CPIs (pharmacy, pesticides, varnishes). It gathers under a single heading products from different types of industries while also illustrating two major characteristics of formulated products: the predominant role of interfaces, given their dispersed structure; the fact that, apart from the active compound and in some cases the solvent phase, most ingredients and=or auxiliaries used tend to develop colloidal properties (i.e. polymers, surfactants, powders). Thus, it can be noted that formulated products have a complex and discontinuous structure, as well as speciŽ c rheological and dynamic properties (the soft matter concept). The key role of the structure of the complex mixtures detailed in Table 1 can be conŽ rmed over a wide range of particle sizes (typically between 0.01 and 100 mm), including colloids. These characteristics are in strong contrast with those of the more conventional products developed in the 19th century (either metallic, mineral or organic), and for which a pseudocontinuous working hypothesis could frequently be assumed. A view of what could be termed the ‘ages’ of chemical product engineering, described above, is summarized in Table 2. Even though numerous formulated products have been empirically developed since antiquity (paints, ink, ointments), this overview highlights the gradual evolution of CPIs to develop processes capable of acting upon more complex states of matter in terms of content, structure and overall behaviour. More generally, synthetic products tend to mimic biological systems, which are mainly heterogeneous structures interacting by weak forces such as Van der Waals or hydrogen bonds.

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Table 2. A simplistic overview of the historical developments of products from human activities based on chemical transformation. Approximate date of appearance 4000 B.P. 1800 1900 1970

Type of product

Key building block

Metals Salts Organic compounds Formulated products

Metallic bond Ionic bond Covalent bond Weak bonds

large body of situations, based on a uniŽ ed framework. This methodology has evolved through the years, but remains a combination of balances, phase equilibria (thermodynamics) and rate equations (mass, heat, or momentum transport, with or without a chemical reaction), as summarised in Figure 2. The recent evolution of CPIs towards complex systems such as formulated products calls for an overview of the scientiŽ c tools which can be used to solve the technical and engineering problems of this industrial sector. As far as formulated products are concerned, a new class of problems has emerged and a tentative survey is proposed below: A great number of operations on formulated products are performed on a batch basis, in contrast to the continuous production processes most often encountered with commodities. Atypical operations such as granulation, compression, extrusion, spray drying, spray chilling, coating, emulsiŽ cation and gelation to name a few, are carried out in place of classical unit operations (e.g. distillation, extraction and absorption). The mixing of complex media (i.e. non Newtonian  uids, particulate solids) is often a core problem.

Chemical Engineering and the Formulated Products Industry Clearly, for commodity products, the chemical engineering approach has proven its ability to efŽ ciently manage a

Figure 2. The foundations of chemical engineering.

Table 1. Characteristics and illustrative composition forms of the three major types of formulated products: A powdered solid (pharmaceutical), a suspension (crop protection) and a gel forming solution (coating). The function aimed by each compound of the formula has been added in italics. Product type

Particulate solids (powders, tablets, granules)

Dispersed liquids (emulsions, dispersions, micelles, latexes)

Soft solids (gels, pastes, solid foams, aerogels)

Continuous phase

Gaseous

Liquid

Solid Network

Dispersed phase

Solid

Solid=Liquid

Liquid=Gaseous

Example and composition

Pharmaceutical tablet Active compound Lactose ( Ž ller) Cellulose ( Ž ller) Polyethyleneglycol (glident) Magnesium stearate (lubricating)

Crop protection liquid Phenylurea (active) Phenolethoxyphosphate (dispersing) Fatty alcohol (wetting) Silicone (antifoam) Propyleneglycol (antifreeze) Water (solvent)

Coating Polyacrylic acid (viscosity enhacer gelling) Titanium oxide (pigment) Aluminium salt (dispersing) Dimethicone (antifoam) Water (solvent)

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FAVRE et al. Structure-property relationships, structure determination and obtaining controlled structures are key challenges. As in classical chemical engineering activities, separation, conversion or yield problems are not major concerns at the production stage. The same pattern applies to reactive systems. In fact, chemical reactivity has to be taken into account only for speciŽ c situations (e.g. delayed reactivity for two part adhesives).

To sum up, issues relevant to formulated products are mostly related to their structural features and to the behavior of complex and heterogeneous media under dynamic conditions, with essentially non reactive contributions. This has led to the appearance of new chemical engineering issues which could be challenged by referring to a core of scientiŽ c knowledge deŽ ning what could be termed ‘product engineering science’: Rheology, especially applied to disordered media and complex mixtures. Transport across interfaces. Structure and behaviour of dispersed systems, including drops, powders and bubbles. Transport phenomena in multicomponent systems. Methodology to investigate micro to macro scale, illustrated for instance through Mashelkar’s seamless paradigm4. Each of these topics has been studied separately during the last decades. Nevertheless, to our knowledge, no handbook presents these in a uniŽ ed form emphasizing a balance=equilibrium=transport processes framework. There is no Perry’s Handbook of Product Engineering5,6. The Chemical Product Engineering Concept In order to deŽ ne the various approach levels encompassing the design and the development of a new formulated product, a schematic framework, applying both to fundamental and applied aspects, is proposed in Figure 3. The Ž rst level is the selection of the various chemicals needed to manufacture the product. This task is typically performed by chemists and physical chemists, and is part of

Figure 3. An overview of product formulation, engineering and design framework.

the formulation activity. Preformulation emerged 15 years ago and deŽ nes the activity of companies which produce and prepare chemicals (not complex mixtures) for a speciŽ c usage in a formulated product. For instance, a calcium carbonate producer (a typical commodity product) can develop special CaCO3 grades in terms of form (calcite or aragonite) and granulometry:Strong abrasive aragonite needlesfor toothpaste or a round shaped calcite for drug excipients. The second step consists of selecting and optimizing the manufacturing process. Besides very simple manufacturing procedures (mixing of miscible phases containing  avors to prepare perfumes), chemical engineering studies are required at this stage (Figure 3). However, the success of the product development is strongly supported by a formulation-chemical engineering integrated approach. The term chemical product engineering, or formulation engineering can be used to describe the methodology appropriate to successfully design new chemical products as shown in the the chemicals=process=product triangle of Figure 3. Particulate solid characteristics for granules production exempliŽ es the compound-process interaction7 (Figure 4). It points out the key role played by only one process operating parameter (i.e. the temperature of a spray cooling chamber) on particle characteristics. When a temperature of 20 C is used, round-shaped and ellipsoidal particles, with a smooth, defect-free surface are obtained. Running the spray dryer at a slightly higher temperature dramatically affects the particle structure: At this temperature, the particle surface is rough and covered by numerous holes, likely to result from droplet separation during the jet break step. These differences can have profound implications either for particle treatment (a rough surface can facilitate binding efŽ ciency during the agglomeration process) or for product use. For example: The defect obtained under high temperature speeds up the dissolution of granules. Makes it difŽ cult to achieve batch to batch consistency. Inhibit the adherence of a protective coating. The strategy underlying chemical product engineering requires a strong interdisciplinary collaboration, which can be highly beneŽ cial but may be difŽ cult to set up4. Food, pharmaceutical companies as well as CPIs have already implemented this collaboration through technical project teams. Finally, the term chemical product design, recently developed by Cussler and Moggridge8 seems to embrace a more holistic strategy, taking into account each formulation and process parameters as well as their relationships as depicted in Figure 3. This includes market identiŽ cation, the selection of ideas, as well as early process and compound selection based on rapid estimations. The deŽ nitions explained above are not shared by the entire scientiŽ c community and they can be qualiŽ ed according to the industry, the country or the author9–13. Therefore, our study of the chemical engineering concept will proceed from a survey of the major research challenges it generates. The relevance of the balance=equilibrium=transport approach will also be evaluated both from a theoretical point of view and in the light of case studies involving pharmaceutical tablet formulation and web coating processes. Trans IChemE, Vol 80, Part A, January 2002

CHEMICAL PRODUCT ENGINEERING PRODUCT ENGINEERING Generic Research Challenges Balances: Extending Existing Tools to SpeciŽc Situations Applying mass, energy or heat transfer balances to formulated products does not appear to be a revolutionary approach. In fact, generic tools have already been developed to apply balance rules to numerous types of situations. However, applying them to the study of formulated products remains difŽ cult due to the complex product composition as well as the predominance of transitory regimens during their manufacture (batch operations). The fact that chemical reactions take place only in rare cases simpliŽ es the writing of equations. Nevertheless, accumulation terms have to be taken into account since formulated products are usually multicomponent and multicompartment systems. An accurate description of compartment properties as well as their evolution with time is required to use mass balance rules. Similarly, working with multicomponent systems demands appropriate analytical or tracking techniques in order to establish and validate mass balances in dispersed structures. Thus, the major bottleneck of the application of balances to chemical products seems to be essentially technical rather than conceptual; accurate investigation tools are needed in order to assess product structure and component distribution. DifŽ culties may arise from the fact that balances sometimes have to deal with distributed properties. For instance, a mass balance on a polymer or a powdered solid may require a detailed examination including molecular weight or size distribution measurements. In these cases, it will be more appropriate to use adapted tools such as population balances or statistical distributions already developed in other Ž elds of chemical engineering (crystallization, polymerization). Equilibrium: Working with Multicomponent, Distributed Properties, Metastable Systems The application of chemical engineering methods to process design Ž rst requires that the characteristics of the system in equilibrium be known. How can we rationally design a distillation column while ignoring the vapourliquid equilibrium curve? Translated into a product engineering situation, this Ž rst step clearly leads to several challenges: i)

ii)

A Ž rst issue is related to the molecules involved in most formulated products. Indeed, they tend to have a complex phase equilibriumbehavior, even if the mixture contains only a few compounds. Thus, the phase diagram of a ternary system including a surfactant, oil and water is more difŽ cult to set up than classical ternary diagrams encountered in liquid-liquid extraction. Even the basic phase equilibrium of a surfactant in solution is still considered a challenging problem for activity coefŽ cient models14. In addition, these systems are often very sensitive to temperatures variations which can induce phase separation during manufacture or storage. Formulated product are multicomponent systems a feature which complicates the thermodynamic approach. SigniŽ cant progress has been achieved in this Ž eld (for instance thanks to group contribution methods or activity coefŽ cient models in liquid

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phases) and distillation columns with multicomponent mixtures can already be designed using thermodynamic-based methods. Moreover, each compound included in formulated products may consist of a population of compounds. Their characteristics are then dispersed around a mean value (Mw for polymers, particle sizes for granules). In these cases, population statistics have to be used within a thermodynamic framework. The theoretical tools of thermodynamics dealing with distribution parameters instead of mean average values are rare but new tools have been proposed recently: Continuous distribution thermodynamics15, phase partitioning of polymers in pores16, incidence of block copolymer distribution on phase equilibrium properties17. Last but not least, the structures created in formulated products are often far removed from their state of equilibrium and are often in a metastable form. This statement applies, among others, to emulsions (apart from microemulsions which are thermodynamically stable), dispersions, amorphous particulate solids and gels. Chemical engineers are bound to issues related to this state and handicapped by the relative lack of scientiŽ c expertise in this largely unexplored Ž eld18. In addition, the underlying problem of the kinetics of change towards equilibrium (creaming of an emulsion, sedimentationof a dispersion, syneresis of a gel, crystallization of a glassy medium) is a major concern where history dependent and often unpredictable dynamic changes are observed (see for example Figure 4).

Dynamics: Predicting Response to Inputs in Complex Systems The complex structure and content of formulated products also in uence their dynamic behaviour: i)

ii)

iii)

From a momentum transport point of view, operations such as mixing or coating are hardly controllable with dispersed and=or non Newtonian mixtures. The pumping process of a dispersion of Ž ne particles in a viscous solution can also dramatically affect the distribution of particles in the bulk  uid (segregation effects can occur) which in turn can induce a sol-gel transition. Similarly, mixing a tiny amount of particles within a bulk powder is extremely difŽ cult to achieve. These typical chemical engineering problems have to be identiŽ ed and solved in order to achieve product quality and especially batch to batch consistency. Countless examples point out how mass transfer dramatically in uences the product make-up (i.e. surfactant diffusion towards the interface for emulsion preparation or suspension stabilisation) or the product end-use properties (controlled release19, wetting dynamics20, delayed reactivity, detergency, fast dissolving). However, multicomponent mass transfer analysis has made signiŽ cant progress recently21 and highly non ideal disordered media appear to be an application Ž eld well-suited to these new concepts. Lastly, a lot of operations on products call upon coupled transport processes. Drying, which combines

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Figure 4. In uence of the operating parameters of a process on product properties; an illustrative example based on the scanning electron microscopy examination of particles obtained by spray cooling: a) cooling chamber temperature ¡ 20 C, b) cooling chamber temperature ¡ 5 C.

heat and mass transfer is a typical example of coupled transport processes and is a common production step (for instance spray drying in solid production, freeze drying in the pharmaceutical industry, air drying applied to coating). Complex mixtures can undergo structural modiŽ cations under drying, depending on process variables such as temperature and processing

times. A study performed a couple of years ago in the Ž eld of silica gel layer formation revealed the complexity of the problem. However, it also pointed out the relevance of chemical engineering methodology applied to transport processes occurring simultaneously with a sol-gel phase transition22. The concept of drying regime maps, derived from this work and Trans IChemE, Vol 80, Part A, January 2002

CHEMICAL PRODUCT ENGINEERING illustrated on Figure 5, could possibly be extended to other systems (i.e. organic coatings). It emphasizes how a tiny change in composition, temperature or gelling kinetics affects the overall process and interferes with the product characteristics (defect-free homogeneous coating, skinning effect or loose deposit). Some emerging challenges in the Ž eld of chemical product formulation and manufacture have been described in the above section. In the last part of this investigation, we shall endeavor to highlight the possibilities and limitations of this methodology through the analysis of case studies. They can be used as illustrations in an introduction course to chemical product engineering as well as indicators of good chemical engineering practice. According to Astarita23, an efŽ cient chemical engineering approach should lead to the selection and the in-depth knowledge of critical manufacturing process steps. EDUCATIONAL CHALLENGES THROUGH WORKING EXAMPLES Methodology: Exploring Product Engineering Science Achievements and Prospects The two case studies featured below aim at underscoring issues chemical engineers face while in operation. Problems or questions arising in operation are understandably quite different from those anticipated by academics. While a rational approach can be proposed to tackle a limited number of the questions, essential parts of the problem have to be treated at the expense of drastic simpliŽ cations or applications of rule of thumbs (often called heuristics when applied to process selection). To that extent, these working examples offer the opportunity to train the chemical engineer to face situations in which decisions have to be taken based on a mix of theoretical knowledge, environment characteristics (budget, time constraints), experience and intuition. Sophisticated investigation techniques or tools could be, in principle, proposed to each item listed below in order to assess a speciŽ c problem. These include computing methods (computational  uid dynamics, molecular dynamics), measuring devices (surface force appara-

tus, dynamic surface tension apparatus) and visualisation techniques (microscopy, nuclear magnetic resonance, light scattering). It can be useful for the student to know the basic principles, potential and limitations of these various tools, even through a simpliŽ ed presentation. Finally, the two case studies presented below could be translated in a conceptual and technical map, showing that the chemical product engineering approach is: 1)

Product speciŽ c;

2)

Capable of warranting the success of the the technical product development; and An in uencing parameter in decision making processes.

3)

Several potential routes can be identiŽ ed, each with speciŽ c pros and cons. The Ž nal decision can only be taken if key criteria are considered, including time and money. The timeframes available for product design are generally much shorter than in classical process development. To that extent, it can be rewarding to let the students deŽ ne the problem themselves, work out their own project plan and be trained to meet deadlines in a development group. Case study 1 A Pharmaceutical Tablet: The Controlled Structure Challenge Form follows function as the ‘architectural dictum’ goes24 and one of the major challenges of companies aiming at developing formulated products such as cars, building, electronics, drug products is to give the expected macro and microscopic structure to a new chemical product5. The design and manufacture study of a fast dissolving pharmaceutical tablet is developed below and illustrates how a chemical product engineering approach can improve the formulation and process development. Two types of information are given as initial inputs to the students: the formulation itself (the compounds involved and their proportion) and the expected end-use properties. These data correspond to the two limits of the general formulation engineering framework proposed in Figure 3 (formula and end-use properties). The Ž rst engineering challenge to address is to Ž nd a compromise between mechanical resistance (decreasing function of overall porosity) and the wetting=dissolution steps (increasing function of overall porosity). Students are then asked to look for key information in books and selected papers in order to: 1) 2) 3)

Figure 5. Schematic drawing of the concept of drying regime maps for a combined gelation-solvent evaporation operation (from Cairncross et al.22 adapted). Number on the curves correspond to the ratio of the gelation kinetics time constant over the drying kinetics time constant (y). Bi refers to Biot number (liquid phase=vapour phase mass transfer resistance) and Da to Damko¨hler number (gelation reaction rate=diffusion rate).

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DeŽ ne a potential manufacturing process and its main steps; Select the critical process and product variables; Select the Ž nished product control tests.

The process steps and critical parameters are presented in Table 3. Useful hints are invariably needed at each stage if one expects the student team to complete the project in a reasonable time. Some of the most crucial heuristics which will guide the process selection are brie y discussed below. A preliminary requirement is to collect basic data about the compounds (thermal sensitivity, solubility, phase partitioning, risk and environmental concern). Classical data-

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bases (Chemical Abstract Services, NIST) or specialised ones (European Pharmacopeia, Cosmetic, Toiletries and Fragrances Association, Codex Alimentarius) can help to Ž gure out the internal (stability) or external (regulations) limitations which have to be taken into account throughout the project. Filling, binding, desintegrating agents have already been selected, thereby mimicking the situation in which the formulation expert has already selected the tablet ingredients and then transferred the project to the process development expert. It should be stressed however that these variables greatly condition the Ž nal properties of the product. To that extent, the modiŽ cations of the composition could be proposed by students if needed to get tablets complying with the requirements. The next step is to identify the critical parameters and optimize them in order to get a fast dissolving tablet. A rule of thumb in this Ž eld is to favour amorphous versus crystalline structures, and thus to promote a metastable form. This can be achieved using solvent mixtures and=or rapid solvent evaporation to precipitate drugs. However, spray drying a lactose=active compound solution would also appear to be an effective process. For heat sensible compounds, freeze drying can be considered a potential alternative. It is nevertheless an expensive process which ends up most of the time in mixtures of cristals and amorphous structures. Dissolution kinetics are also strongly related to tablet structural parameters such as porosity or liquid wetting kinetics. A more quantitative approach can be proposed at this stage, based on the so-called Washburn equation, in which the interplay between pore diameter (d), liquid viscosity (Z) and interfacial tension (s) is evidenced25. The time needed to wet a pore of length z can be computed in principle from: 4Z z2 t 1 s d The expression above is not easily applicable to a porous medium characterized by pore size distribution. A modiŽ ed equation which makes use of porosity instead of pore diameter can be proposed26: hK a 1 e Z z2 2 e s cos y Rapid estimations can be performed to select an appropriate range of porosity values in order to fulŽ l the dissolu-

t

tion criteria. Typically, Ž gures between 0.2 and 0.5 are obtained as a Ž rst guess. Complex mixing laws which govern the effective achievable porosity when non uniform and=or non spherical particles are ‘glued’ together can be extensively studied at this juncture. The complexity of the granulation process can also be commented based on recent state-of-the-art studies27. Next, it is advisable to look into tablet mechanical resistance. Pressure-densiŽ cation relationships seem difŽ cult to predict in products obtained by compaction28. The considerable differences between cosmetic make-up and pharmaceutical tablet compression can be discussed at this stage: The former demands a pressure of around 10 bar for 1 second, while the latter requires a 1000 bar working pressure for less than 1 millisecond. In the latter case, the binding mechanism of granules is still not accurately described nor modelized. Soft amorphous particulate solids based on sugars (obtained by spray drying) are often more appropriate than hard, crystalline, pure compounds29. A fast dissolution rate and a mechanical stability should be obtained by manufacturing tablets with compacted granules prepared by spray drying the drug and with the excipient. Spray-drying lactose with active compound should generate porous particles process, while the compaction process operating between 10 and 100 MPa should yield tablets of optimal mechanical resistance (0.2 < e < 0.5). This example stresses the importance of chemical product engineering in preformulation (particulate solid production) as well as in tablet manufacturing phases. Case study 2. Interplay of Formulation and End-Use Properties in Web Coating This second case study deals with the formulation and manufacturing process development of a solution dedicated to roll web coating application on smooth surfaces (e.g. a plastic Ž lm). The list of ingredients as well as the key targeted end use properties (summarized in Table 4) are given to students at the beginning of the project. The following items can be investigated, based on individual or team work: i)

The main operation implemented in the manufacturing process is a mixing operation. How do you proceed?

Table 3. Pharmaceutical tablet case study: Conceptual framework. Starting information

Tablet composition: Active compound, Lactose, Microcrystalline cellulose, ModiŽ ed starch, Polyethyleneglycol, Magnesium stearate

Targeted end-use properties: Dissolution in less than 20 s at 20 C in water, Crushing strength >1.5 MPa

Item

Key concept

Techniques

Compounds: Physical and chemical properties Granulate selection Tablet production End-use property

Granulometry, Crystallinity, Compressibility, Wettability Swelling, Compatibility Density, Porosity, Crystallinity, Flowability Compression laws, Melting point, Heat capacity, Elasticity Wetting, Dissolution (amorphous vs crystalline), Mechanical strength, Bioavailability

Laser light scattering, X ray diffraction, Contact angle, Solubility Wet granulation (mixer,  uidised bed), Dry granulation, Spray drying, freeze drying Pressure densiŽ cation, Bulk density, Calorimetry, Strain=stress curve Hg porosimetry, Turbidimetry, In vitro drug release, Pharmacokinetics

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ii) iii) iv)

(which compounds do you add Ž rst? What type of mixing apparatus do you use?) How do you ensure correct product stability during storage in terms of sedimentation or  occulation? How does viscosity and surface tension affect the coating process? What is the implication of a nonNewtonian behaviour and when will it appear? How do you manage the drying step? Does it signiŽ cantly affect the appearance of the Ž nal product aspect and its end-use properties?

For coating application, a simple approach resorts to a capillary number30: Z u Ca 3 s Recent advances show that the capillary number should not exceed a critical value if a defect-free coating (i.e. smooth, non wavy surface) is expected, as depicted in Figure 631. This adimensional number illustrates the relationships between formulation and process variables as well as their impact on the properties of the Ž nal product: formulation changes  oculation or sedimentation rates, induces viscosity and=or surface tension changes which will affect a coating operation. The web coating speed u has to be changed and adapted to new conditions. However, surface tension can only slightly change to fulŽ ll the wetting criteria (contact angle). Finally, the viscosity should be high enough to prevent particle sedimentation, but low enough to prevent sol-gel transition. Paying attention to this parameter makes it possible to explain the conceptual framework underlying sol-gel transition (mean Ž eld or percolation theory) as well as to bring to light general guidelines concerning the in uence of parameters on this value (temperature, polymer molecular weight, concentration). The importance of the drying step can also be illustrated. The concept of drying maps, taking a combined gelationevaporation mechanism into account can be developed (Figure 5). The incidence of the drying regime upon the coating structure can be estimated through simpliŽ ed calculations. This case study emphasizes the complexity of the selection and the optimization of the formulation and manufac-

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turing process development phases. In particular, formulation and manufacturing may require con icting solutions. This example can therefore help to convince students that the solvity of the product development issues requires both an interdisciplinary approach (team work) and a strong background in chemical engineering. CONCLUSION According to Danckwerts, chemical engineering is a lively engineering science which has to32: Maintain a strong identity through novel concepts based on novel scientiŽ c grounds; and Keep in touch with the challenges and problems of the chemical process industries (CPIs). The Ž rst criterion leads to the concept of paradigm, frequently proposed as a major historical landmark in the evolution of a discipline33,34. Unit operations, often considered the Ž rst unifying paradigm of chemical engineering, appeared around 192435. It is generally recognized that the second paradigm appeared in 1960 with the book of Bird, Stewart and Lightfoot entitled ‘Transport phenomena’36. Today, the second paradigm is as old as the Ž rst one was when this book was published and the

Figure 6. Imperfect (ribbing) vs uniform coating regimes in forward roll coating through the capillary number concept (from Coyle et al.31, adapted).

Table 4. Web coating case study: Conceptual framework. Starting information

Composition: titanium oxide, polyacrylic acid, aluminium salt, dimethicone, water

Targeted end-use properties: Defect free coating for web roll applications, Fast drying

Item

Key concept

Techniques

Pure compounds: physical and chemical properties Mixing Coating process Drying

Storage

Granulometry, Density, Viscosity, Wettability, Surface tension, Water solubility Role of sequential addition, Mixing of dispersions, Gel point Wetting statics and dynamics, Capillary number Sol-gel transition, Coupled heat and mass transfer (drying maps) Adhesion Sedimentation in non Newtonian liquid, Flocculation

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Rheometer, Surface tension, Pycnometer, Size distribution Laboratory mixing tests, Visualisation techniques, Polymers on solid surfaces Contact angle, Web surface properties Gel point measurement, Surface temperature (drying), Peel test Zeta potential, Sedimentometer

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chemical engineering community is still searching for the elusive third paradigm 4,34,37. The needs of modern society, a multiscale approach, biology, manufacturing efŽ ciency are all held out as promising challenges from which novel concepts could emerge. The second criterion encourages the development of chemical product engineering science. This challenging and still embryonic discipline could act as a product driven science merging several of the areas identiŽ ed above as promising tracks for chemical engineering (working with multiscale problems, facing complex matter behaviour, trying to fulŽ l society’s needs, controlling manufacturing processes, mimicking biological systems38–40). Chemical product engineering may thus constitute an interdisciplinary approach to product design, manufacturing and characterizing, requiring in-depth knowledge of process and colloidal chemistry as well as the capacity to select the right ingredient for the right process at the right time and place. NOMENCLATURE a Bi Ca Da G hK u t z

speciŽ c surface area, m¡1 Biot number capillary number Da¨mkohler number ratio of the gap between the rolls to the roll diameter Khozeny constant web speed, m s¡1 time, s granule thickness, m

Greek symbols e porosity Z viscosity, Pa s s surface tension, N m¡1 y contact angle

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ACKNOWLEDGEMENTS The authors wish to thank Geoffrey Sockett for skilful assistance, as well as the referees for their valuable comments on the manuscript.

ADDRESS Correspondence concerning this paper should be addressed to Dr E. Favre, Groupe ENSIC, INPL, 1 rue Grandville, 54001 Nancy, France. E-mail: [email protected] The manuscript was received 2 July 2001 and accepted for publication after revision 5 November 2001.

Trans IChemE, Vol 80, Part A, January 2002