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O. D. Putra and H. Uekusa
9.1.2 Challenges of Solid APIs
In the pharmaceutical industry, one of the bottlenecks in the discovery and development of APIs is the optimization of drug product performance by pre-formulation
research [29, 30]. The goal of pre-formulation research is to provide optimized APIs
featuring suitable physiological profiles that can later be formulated into pharmaceutical dosage forms [31, 32]. As mentioned before, APIs are most commonly
formulated in solid form, i.e., tablets, capsules, and granules, because the chemical stability is superior to that of a solution. Furthermore, solid-state dosage forms
provide more practical processing, packaging, handling, and allow, for most patients,
the preferred choice of drug intake, oral delivery.
Solid APIs are generally used for dosage forms intended for oral delivery. It should
be noted that oral delivery typically requires the dissolution of active ingredients at
the absorption site, while avoiding precipitation during gastrointestinal transit, until
complete absorption [33]. Unfortunately, about 40% of marketed drugs and almost
double the percentage of drug candidates are thought to have solubility issues in
oral administration [34, 35]. Meanwhile, many solid APIs exhibit other unfavorable
physicochemical properties, such as hygroscopicity, [36] brittleness, [37] and chemical instability, [38] which become a problem during manufacturing and storage.
In general, low solubility and stability pose a serious threat for candidate APIs
by preventing the drug from reaching minimum therapeutic concentrations in the
biological system [39–41].
Moreover, some drugs exhibit more than one unfavorable physicochemical property, creating the need for an ultimate simultaneous solution. Hygroscopicity is
considered an unfavorable physicochemical property, which leads to increased
production costs. By far, the biggest challenge posed hygroscopicity is the extra effort
required to dry the APIs during processing and then before packaging. The judicious
use of production rooms with controlled humidity and sealed packaging systems is
advisable in many cases [42]. Brittleness is another hostile physicochemical property
that is mostly related to processing bulk APIs. Difficulties due to brittleness often
arise during milling, filling, and compaction, due to the poor mechanical properties
of bulk powders [43]. The physicochemical properties of insolubility and chemical
instability are strongly negatively related to the safety, quality, and efficacy of APIs
[44, 45].
Some approaches that tackle these unfavorable physicochemical properties can
be divided into formulation, particle engineering, and crystal engineering (Fig. 9.2).
In formulation, an API is combined with other substances or excipients to optimize
the physicochemical properties, therapeutic potential, safety, and stability of the
final dosage form. The formulation of the drug also covers the processing methods
and devices, and the packaging [46]. Particle engineering involves the methodology
used to obtain the optimal particle size, size distribution, morphology, and surface
characteristics. Particle engineering can cover all aspects that modify the morphology
and surface behavior of a drug, with or without the addition of excipients [47, 48].
O. D. Putra and H. Uekusa
9.1.2 Challenges of Solid APIs
In the pharmaceutical industry, one of the bottlenecks in the discovery and development of APIs is the optimization of drug product performance by pre-formulation
research [29, 30]. The goal of pre-formulation research is to provide optimized APIs
featuring suitable physiological profiles that can later be formulated into pharmaceutical dosage forms [31, 32]. As mentioned before, APIs are most commonly
formulated in solid form, i.e., tablets, capsules, and granules, because the chemical stability is superior to that of a solution. Furthermore, solid-state dosage forms
provide more practical processing, packaging, handling, and allow, for most patients,
the preferred choice of drug intake, oral delivery.
Solid APIs are generally used for dosage forms intended for oral delivery. It should
be noted that oral delivery typically requires the dissolution of active ingredients at
the absorption site, while avoiding precipitation during gastrointestinal transit, until
complete absorption [33]. Unfortunately, about 40% of marketed drugs and almost
double the percentage of drug candidates are thought to have solubility issues in
oral administration [34, 35]. Meanwhile, many solid APIs exhibit other unfavorable
physicochemical properties, such as hygroscopicity, [36] brittleness, [37] and chemical instability, [38] which become a problem during manufacturing and storage.
In general, low solubility and stability pose a serious threat for candidate APIs
by preventing the drug from reaching minimum therapeutic concentrations in the
biological system [39–41].
Moreover, some drugs exhibit more than one unfavorable physicochemical property, creating the need for an ultimate simultaneous solution. Hygroscopicity is
considered an unfavorable physicochemical property, which leads to increased
production costs. By far, the biggest challenge posed hygroscopicity is the extra effort
required to dry the APIs during processing and then before packaging. The judicious
use of production rooms with controlled humidity and sealed packaging systems is
advisable in many cases [42]. Brittleness is another hostile physicochemical property
that is mostly related to processing bulk APIs. Difficulties due to brittleness often
arise during milling, filling, and compaction, due to the poor mechanical properties
of bulk powders [43]. The physicochemical properties of insolubility and chemical
instability are strongly negatively related to the safety, quality, and efficacy of APIs
[44, 45].
Some approaches that tackle these unfavorable physicochemical properties can
be divided into formulation, particle engineering, and crystal engineering (Fig. 9.2).
In formulation, an API is combined with other substances or excipients to optimize
the physicochemical properties, therapeutic potential, safety, and stability of the
final dosage form. The formulation of the drug also covers the processing methods
and devices, and the packaging [46]. Particle engineering involves the methodology
used to obtain the optimal particle size, size distribution, morphology, and surface
characteristics. Particle engineering can cover all aspects that modify the morphology
and surface behavior of a drug, with or without the addition of excipients [47, 48].